Sulfonimidoylpurinone Compounds

ABSTRACT

The present invention relates to compounds of formula (I), 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1 , R 2  and R 3  are as described herein, and their prodrugs or pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds.

RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.15/621,080, filed Jun. 13, 2017, which is a Continuation of U.S.application Ser. No. 15/148,309, filed May 6, 2016, now U.S. Pat. No.9,708,325, claiming priority to International Application numberPCT/CN2016/078785 filed Apr. 8, 2016, and International Application No.PCT/CN2015/078507 filed May 8, 2015, the contents of which areincorporated herein by reference.

The present invention relates to novel sulfonimidoylpurinones and theirderivatives that have Toll-like receptor agonism activity and theirprodrugs thereof, as well as their manufacture, pharmaceuticalcompositions containing them and their potential use as medicaments.

FIELD OF THE INVENTION

The present invention relates to compounds of formula (I),

-   -   and their prodrugs, formula (Ia),

-   -   wherein R¹ to R⁸ are described below, or pharmaceutically        acceptable salt, enantiomer or diastereomer thereof.

Toll-like receptors (TLRs) detect a wide range of conservedpathogen-associated molecular patterns (PAMPs). They play an importantrole of sensing invading pathogens and subsequent initiation of innateimmune responses. There are 10 known members of the TLR family in human,which are type I transmembrane proteins featuring an extracellularleucine-rich domain and a cytoplasmic tail that contains a conservedToll/interleukin (IL)-1 receptor (TIR) domain. Within this family, TLR3,TLR7 TLR8, and TLR9 are located within endosomes. TLR7 can be activatedby binding to a specific small molecule ligand (i.e., TLR7 agonist) orits native ligand (i.e., single-stranded RNA, ssRNA). Following bindingof ssRNA to TLR7, the receptor in its dimerized form is believed toundergo a structural change leading to the subsequent recruitment ofadapter proteins at its cytoplasmic domain, including the myeloiddifferentiation primary response gene 88 (MyD88). Following theinitiation of the receptor signalling cascade via the MyD88 pathway,cytoplasmic transcription factors such as interferon regulatory factor 7(IRF-7) and nuclear factor kappa B (NF-κB) are activated. Thesetranscription factors then translocate to the nucleus and initiate thetranscription of various genes, e.g., IFN-α and other antiviral cytokinegenes. TLR7 is predominately expressed on plasmacytoid cells, and alsoon B-cells. Altered responsiveness of immune cells might contribute tothe reduced innate immune responses during chronic viral infections.Agonist-induced activation of TLR7 might therefore represent a novelapproach for the treatment of chronic viral infections. (D. J Connollyand L. A J O'Neill, Current Opinion in Pharmacology 2012, 12:510-518, P.A. Roethle et al, J. Med. Chem. 2013, 56, 7324-7333).

The current therapy of chronic HBV infection is based on two differenttypes of drugs: the traditional antiviral nucleos(t)ide analogues andthe more recent Pegylated IFN-α (PEG-IFN-α). The oral nucleos(t)ideanalogues act by suppressing the HBV replication. This is a life-longcourse of treatment during which drug resistance often occurs. As analternative option, Pegylated IFN-α (PEG-IFN-α) has been used to treatsome chronic infected HBV patients within finite therapy duration.Although it has achieved seroconversion in HBeAg at least in a smallpercentage of HBV patients, the adverse effect makes it poorlytolerable. Notably, functional cure defined as HBsAg seroconversion isvery rare with both current therapies. A new generation therapeuticoption to treat HBV patients for a functional cure is therefore ofurgent need. Treatment with an oral TLR7 agonist represents a promisingsolution to provide greater efficacy with better tolerability. PegylatedIFN-α (PEG-IFN-α) is currently used to treat chronic HBV and is analternative to potentially life-long treatment with antiviralnucleos(t)ide analogues. In a subset of chronic HBV patients, PEG-IFN-αtherapy can induce sustained immunologic control of the virus followinga finite duration of therapy. However, the percentage of HBV patientsthat achieve seroconversion with interferon therapy is low (up to 27%for HBeAg-positive patients) and the treatment is typically poorlytolerated. Furthermore, functional cure (defined as HBsAg loss andseroconversion) is also very infrequent with both PEG-IFN-α andnucleos(t)ide treatment. Given these limitations, there is an urgentneed for improved therapeutic options to treat and induce a functionalcure for chronic HBV. Treatment with an oral, small-molecule TLR7agonist is a promising approach that has the potential to providegreater efficacy and tolerability (T. Asselah et al, Clin Liver Dis2007, 11, 839-849).

In fact, several identified TLR7 agonists have been considered fortherapeutic purposes. So far Imiquimod (ALDARA™) is a U.S. FDA approvedTLR7 agonist drug for topical use to treat skin lesions by humanpapillomavirus. The TLR7/8 dual agonist resiquimod (R-848) and the TLR7agonist 852A have been evaluated for treating human genital herpes andchemotherapy-refractory metastatic melanoma, respectively. ANA773 is anoral pro-drug TLR7 agonist, developed for the treatment of patients withchronic hepatitis C virus (HCV) infection and chronic hepatitis Binfection. GS-9620 is an orally available TLR7 agonist. A phase Ib studydemonstrated that treatment with GS-9620 was safe, well tolerated andresulted in dose-dependent ISG15 mRNA induction in patients with chronichepatitis B (E. J. Gane et al, Annu Meet Am Assoc Study Liver Dis(November 1-5, Washington, D.C.) 2013, Abst 946). Therefore there ishigh unmet clinical need for developing potent and safe TLR7 agonists asnew HBV treatment to offer more therapeutic solutions or replaceexisting partly effective treatment.

SUMMARY OF THE INVENTION

The present invention provides a series of novel6-amino-2-sulfonimidoyl-9-substituted-7H-purin-8-one compounds that haveToll-like receptor agonism activity and their prodrugs. The inventionalso provides the bio-activity of such compounds to induce SEAP levelincrease by activating Toll-like receptors, such as TLR7 receptor, themetabolic conversion of prodrugs to parent compounds in the presence ofhuman hepatocytes, and the therapeutic or prophylactic use of suchcompounds and their pharmaceutical compositions comprising thesecompounds and their prodrugs to treat or prevent infectious disease likeHBV or HCV. The present invention also provides compounds with superioractivity. In addition, the compounds of formula (I) and/or (Ia) alsoshow good solubility, selectivity over TLR8, in vitro and in vivoclearance, Ames, hERG, GSH, PK and safety profiles.

The present invention relates to novel compounds of formula (I),

-   -   wherein

-   R¹ is C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₇cylcoalkylC₁₋₆alkyl,    C₁₋₆alkoxyC₁₋₆alkyl or pyrrolidinylC₁₋₆alkyl;

-   R² is C₁₋₆alkyl, phenylC₁₋₆alkyl, pyridinylC₁₋₆alkyl or    pyrimidinylC₁₋₆alkyl, said phenylC₁₋₆alkyl, pyridinylC₁₋₆alkyl and    pyrimidinylC₁₋₆alkyl are unsubstituted or substituted by one, two or    three substituents independently selected from halogen, C₁₋₆alkyl,    C₁₋₆alkoxy, cyano, carboxy, carbamoyl, haloC₁₋₆alkyl,    C₁₋₆alkylsulfonyl, C₁₋₆alkoxycarbonyl,    C₁₋₆alkoxyC₁₋₆alkylaminocarbonyl, pyrrolidinylcarbonyl and    piperidinylcarbonyl;

-   R³ is H;    or pharmaceutically acceptable salt, enantiomer or diastereomer    thereof.

The present invention also relates to the prodrugs of formula (Ia),

wherein

-   R⁴ is C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₇cylcoalkylC₁₋₆alkyl,    C₁₋₆alkoxyC₁₋₆alkyl or pyrrolidinylC₁₋₆alkyl;-   R⁵ is C₁₋₆alkyl, phenylC₁₋₆alkyl, pyridinylC₁₋₆alkyl or    pyrimidinylC₁₋₆alkyl, said phenylC₁₋₆alkyl, pyridinylC₁₋₆alkyl and    pyrimidinylC₁₋₆alkyl are unsubstituted or substituted by one, two or    three substituents independently selected from halogen, C₁₋₆alkyl,    C₁₋₆alkoxy, cyano, carboxy, carbamoyl, haloC₁₋₆alkyl,    C₁₋₆alkylsulfonyl, C₁₋₆alkoxycarbonyl,    C₁₋₆alkoxyC₁₋₆alkylaminocarbonyl, pyrrolidinylcarbonyl and    piperidinylcarbonyl;-   R⁶ is H or C₁₋₆alkyl-C(O)O—C₁₋₆alkyl-;-   R⁷ is H, C₁₋₆alkyl, C₃₋₇cycloalkyl or C₁₋₁₀alkylcarbonyl;-   R⁸ is H, C₁₋₆alkylcarbonyl, carboxyC₁₋₆alkylcarbonyl,    C₁₋₆alkyoxycarbonylC₁₋₆alkylcarbonyl or benzoyl;    or pharmaceutically acceptable salt, enantiomer or diastereomer    thereof.

The invention also relates to their manufacture, medicaments based on acompound in accordance with the invention and their production as wellas the use of compounds of formula (I) or their prodrugs, formula (Ia),thereof as TLR7 agonist. Accordingly, the compounds of formula (I) ortheir prodrugs, formula (Ia), are useful for the treatment orprophylaxis of HBV and/or HCV infection with Toll-like receptorsagonism.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Furthermore, the followingdefinitions are set forth to illustrate and define the meaning and scopeof the various terms used to describe the invention.

Definitions

The term “C₁₋₆alkyl” denotes a saturated, linear or branched chain alkylgroup containing 1 to 6, particularly 1 to 4 carbon atoms, for examplemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl andthe like. Particular “C₁₋₆alkyl” groups are methyl, ethyl and n-propyl.

The term “C₁₋₁₀alkyl” denotes a saturated, linear or branched chainalkyl group containing 1 to 10, particularly 1 to 7 carbon atoms,Particular “C₁₋₁₀alkyl” group is propylbutyl.

The term “C₃₋₇cycloalkyl” denotes to a saturated carbon ring containingfrom 3 to 7 carbon atoms, particularly from 3 to 6 carbon atoms, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Particular “C₃₋₇cycloalkyl” group is cyclopropyl.

The term “C₁₋₆alkoxy” denotes a group of the formula C₁₋₆alkyl-O—.Examples of C₁₋₆alkoxy group include, but not limited to, methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.Particular “C₁₋₆alkoxy” groups are methoxy, ethoxy and isopropoxy. Amore particular C₁₋₆alkoxy group is ethoxy.

The term “halogen” and “halo” are used interchangeably herein and denotefluoro, chloro, bromo, or iodo.

The term “haloC₁₋₆alkyl” denotes an alkyl group wherein at least one ofthe hydrogen atoms of the alkyl group has been replaced by same ordifferent halogen atoms, particularly fluoro atoms. Examples ofhaloC₁₋₆alkyl include monofluoro-, difluoro- or trifluoro-methyl, -ethylor -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl,2,2,2-trifluoroethyl, fluoromethyl, difluoromethyl, trifluoromethyl andtrifluoroethyl.

The term “amino” denotes a group of the formula —NR′R″ wherein R′ and R″are independently hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₇cycloalkyl,heteroC₃₋₇cycloalkyl, aryl or heteroaryl. Alternatively, R′ and R″,together with the nitrogen to which they are attached, can form aheteroC₃₋₇cycloalkyl. The term “primary amino” denotes a group whereinboth R′ and R″ are hydrogen. The term “secondary amino” denotes a groupwherein R′ is hydrogen and R″ is not. The term “tertiary amino” denotesa group wherein both R′ and R″ are not hydrogen. Particular secondaryand tertiary amino are methylamino, ethylamino, propylamino,isopropylamino, phenylamino, benzylamino dimethylamino, diethylamino,dipropylamino, diisopropylamino, methoxyethylamino, methylethylamino,chlorobutylmethyl amino, dibutylamino and methylbutylamino.

The term “carbonyl” alone or in combination refers to the group —C(O)—.

The term “C₁₋₆alkylcarbonyl” refers to a group C₁₋₆alkyl-C(O)—, whereinthe “C₁₋₆alkyl” is as defined above. Particular “C₁₋₆alkylcarbonyl”group is acetyl.

The term “enantiomer” denotes two stereoisomers of a compound which arenon-superimposable mirror images of one another.

The term “diastereomer” denotes a stereoisomer with two or more centersof chirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities.

The term “pharmaceutically acceptable salts” denotes salts which are notbiologically or otherwise undesirable. Pharmaceutically acceptable saltsinclude both acid and base addition salts.

The term “pharmaceutically acceptable acid addition salt” denotes thosepharmaceutically acceptable salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid, and organic acids selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic, and sulfonic classes of organic acids such as formic acid,acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid,pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid,succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid,ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamicacid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonicacid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid.

The term “pharmaceutically acceptable base addition salt” denotes thosepharmaceutically acceptable salts formed with an organic or inorganicbase. Examples of acceptable inorganic bases include sodium, potassium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, andaluminum salts. Salts derived from pharmaceutically acceptable organicnontoxic bases includes salts of primary, secondary, and tertiaryamines, substituted amines including naturally occurring substitutedamines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, and polyamine resins.

Compounds of the general formula (I) and their prodrugs which containone or several chiral centers can either be present as racemates,diastereomeric mixtures, or optically active single isomers. Theracemates can be separated according to known methods into theenantiomers. Particularly, diastereomeric salts which can be separatedby crystallization are formed from the racemic mixtures by reaction withan optically active acid such as e.g. D- or L-tartaric acid, mandelicacid, malic acid, lactic acid or camphorsulfonic acid.

The term “prodrug” denotes a form or derivative of a compound which ismetabolized in vivo, e.g., by biological fluids or enzymes by a subjectafter administration, into a pharmacologically active form of thecompound in order to produce the desired pharmacological effect.Prodrugs are described e.g. in “The Organic Chemistry of Drug Design andDrug Action”, by Richard B. Silverman, Academic Press, San Diego, 2004,Chapter 8 Prodrugs and Drug Delivery Systems, pp. 497-558.

“A pharmaceutically active metabolite” is intended to mean apharmacologically active product produced through metabolism in the bodyof a specified compound or salt thereof. After entry into the body, mostdrugs are substrates for chemical reactions that may change theirphysical properties and biologic effects. These metabolic conversions,which usually affect the polarity of the compounds of the invention,alter the way in which drugs are distributed in and excreted from thebody. However, in some cases, metabolism of a drug is required fortherapeutic effect.

The term “therapeutically effective amount” denotes an amount of acompound or molecule of the present invention that, when administered toa subject, (i) treats or prevents the particular disease, condition ordisorder, (ii) attenuates, ameliorates or eliminates one or moresymptoms of the particular disease, condition, or disorder, or (iii)prevents or delays the onset of one or more symptoms of the particulardisease, condition or disorder described herein. The therapeuticallyeffective amount will vary depending on the compound, the disease statebeing treated, the severity of the disease treated, the age and relativehealth of the subject, the route and form of administration, thejudgement of the attending medical or veterinary practitioner, and otherfactors.

The term “pharmaceutical composition” denotes a mixture or solutioncomprising a therapeutically effective amount of an activepharmaceutical ingredient together with pharmaceutically acceptableexcipients to be administered to a mammal, e.g., a human in needthereof.

TLR7 Agonist and Prodrug

The present invention relates to a compound of formula (I),

wherein

-   R¹ is C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₇cylcoalkylC₁₋₆alkyl,    C₁₋₆alkoxyC₁₋₆alkyl or pyrrolidinylC₁₋₆alkyl;-   R² is C₁₋₆alkyl, phenylC₁₋₆alkyl, pyridinylC₁₋₆alkyl or    pyrimidinylC₁₋₆alkyl, said phenylC₁₋₆alkyl, pyridinylC₁₋₆alkyl and    pyrimidinylC₁₋₆alkyl are unsubstituted or substituted by one, two or    three substituents independently selected from halogen, C₁₋₆alkyl,    C₁₋₆alkoxy, cyano, carboxy, carbamoyl, haloC₁₋₆alkyl,    C₁₋₆alkylsulfonyl, C₁₋₆alkoxycarbonyl,    C₁₋₆alkoxyC₁₋₆alkylaminocarbonyl, pyrrolidinylcarbonyl and    piperidinylcarbonyl;-   R³ is H;    or pharmaceutically acceptable salt, enantiomer or diastereomer    thereof.

A further embodiment of present invention is (ii) a compound of formula(I), wherein R¹ is methyl, ethyl, propyl, butyl, chloropropyl,cyclohexylmethyl, methoxyethyl, methoxypropyl, pyrrolidinylpropyl ortrifluoroethyl; R² is isobutyl, benzyl, chlorobenzyl, fluorobenzyl,bromobenzyl, chlorofluorobenzyl, chloromethylbenzyl, dichlorobenzyl,difluorobenzyl, methylbenzyl, methoxybenzyl, cyanobenzyl,carbamoylbenzyl, trifluoromethylbenzyl, methyl sulfonylbenzyl,methoxycarbonylbenzyl, carboxybenzyl, methoxyethylaminocarbonylbenzyl,piperidinylcarbonylbenzyl, pyrrolidinylcarbonylbenzyl, pyridinylmethyl,chloropyridinylmethyl, methylpyridinylmethyl, pyrimidinylmethyl ormethylpyrimidinylmethyl;

-   R³ is H;    or pharmaceutically acceptable salt, enantiomer or diastereomer    thereof.

A further embodiment of present invention is (iii) a compound of formula(I), wherein R¹ is C₁₋₆alkyl, haloC₁₋₆alkyl or C₁₋₆alkoxyC₁₋₆alkyl; orpharmaceutically acceptable salt, enantiomer or diastereomer thereof.

A further embodiment of present invention is a compound of formula (I),wherein R¹ is methyl, propyl, chloropropyl, methoxyethyl ortrifluoroethyl; or pharmaceutically acceptable salt, enantiomer ordiastereomer thereof.

A further embodiment of present invention is (iv) a compound of formula(I), wherein R¹ is methyl, ethyl, propyl, butyl, chloropropyl,trifluoroethyl, methoxyethyl or methoxypropyl; or pharmaceuticallyacceptable salt, enantiomer or diastereomer thereof.

A further embodiment of present invention is (v) a compound of formula(I), wherein R¹ is C₁₋₆alkyl; or pharmaceutically acceptable salt,enantiomer or diastereomer thereof.

A further embodiment of present invention is (vi) a compound of formula(I), wherein R¹ is methyl, ethyl or propyl; or pharmaceuticallyacceptable salt, enantiomer or diastereomer thereof.

A further embodiment of present invention is (vii) a compound of formula(I), wherein R¹ is ethyl; or pharmaceutically acceptable salt,enantiomer or diastereomer thereof.

A further embodiment of present invention is a compound of formula (I),wherein R² is phenylC₁₋₆alkyl, said phenylC₁₋₆alkyl is unsubstituted orsubstituted by one to three substituents independently selected fromhalogen, C₁₋₆alkyl, carboxy and C₁₋₆alkoxycarbonyl; or pharmaceuticallyacceptable salt, enantiomer or diastereomer thereof.

A further embodiment of present invention is (viii) a compound offormula (I), wherein R² is phenylC₁₋₆alkyl, said phenylC₁₋₆alkyl isunsubstituted or substituted by halogen, carbamoyl, C₁₋₆alkyl, carboxy,cyano, C₁₋₆alkoxy, C₁₋₆alkylsulfonyl andC₁₋₆alkoxyC₁₋₆alkylaminocarbonyl; pyridinylC₁₋₆alkyl, saidpyridinylC₁₋₆alkyl is unsubstituted or substituted by C₁₋₆alkyl; orpyrimidinylC₁₋₆alkyl, said pyrimidinylC₁₋₆alkyl is unsubstituted orsubstituted by C₁₋₆alkyl; or pharmaceutically acceptable salt,enantiomer or diastereomer thereof.

A further embodiment of present invention is (ix) a compound of formula(I), wherein R² is benzyl, methylbenzyl, chlorobenzyl, fluorobenzyl,difluorobenzyl, cyanobenzyl, carboxybenzyl, methoxybenzyl,methylsulfonylbenzyl, methoxyethylaminocarbonylbenzyl, pyridinylmethyl,methylpyridinylmethyl, pyrimidinylmethyl or methylpyrimidinylmethyl; orpharmaceutically acceptable salt, enantiomer or diastereomer thereof.

A further embodiment of present invention is a compound of formula (I),wherein R² is benzyl, methylbenzyl, chlorobenzyl, fluorobenzyl,bromobenzyl, chlorofluorobenzyl, chloromethylbenzyl, dichlorobenzyl,difluorobenzyl, carboxybenzyl or methoxycarbonylbenzyl; orpharmaceutically acceptable salt, enantiomer or diastereomer thereof.

A further embodiment of present invention is (x) a compound of formula(I), wherein R² is benzyl, methylbenzyl, chlorobenzyl, fluorobenzyl,difluorobenzyl, carboxybenzyl or methylpyridinylmethyl; orpharmaceutically acceptable salt, enantiomer or diastereomer thereof.

A further embodiment of present invention is (xi) a compound of formula(I), wherein R² is methylbenzyl or chlorobenzyl; or pharmaceuticallyacceptable salt, enantiomer or diastereomer thereof.

Another embodiment of present invention is (xii) a compound of formula(I), wherein

-   R¹ is C₁₋₆alkyl or C₁₋₆alkoxyC₁₋₆alkyl;-   R² is phenylC₁₋₆alkyl, said phenylC₁₋₆alkyl is unsubstituted or    substituted by halogen, carbamoyl, C₁₋₆alkyl, carboxy, cyano and    C₁₋₆alkoxyC₁₋₆alkylaminocarbonyl; or pyrimidinylC₁₋₆alkyl, said    pyrimidinylC₁₋₆alkyl is unsubstituted or substituted by C₁₋₆alkyl;-   R³ is H;    or pharmaceutically acceptable salt, enantiomer or diastereomer    thereof.

A further embodiment of present invention is (xiii) a compound offormula (I), wherein

-   R¹ is methyl, ethyl, propyl, butyl or methoxyethyl;-   R² is benzyl, methylbenzyl, chlorobenzyl, fluorobenzyl, cyanobenzyl,    carboxybenzyl, methoxyethylaminocarbonylbenzyl, pyrimidinylmethyl or    methylpyrimidinylmethyl;-   R³ is H;    or pharmaceutically acceptable salt, enantiomer or diastereomer    thereof.

Another embodiment of present invention is (xiv) a compound of formula(I), wherein

-   R¹ is C₁₋₆alkyl;-   R² is phenylC₁₋₆alkyl, said phenylC₁₋₆alkyl is unsubstituted or    substituted by halogen or C₁₋₆alkyl;-   R³ is H;    or pharmaceutically acceptable salt, enantiomer or diastereomer    thereof.

A further embodiment of present invention is (xv) a compound of formula(I), wherein

-   R¹ is ethyl or propyl;-   R² is benzyl, chlorobenzyl or methylbenzyl;-   R³ is H;    or pharmaceutically acceptable salt, enantiomer or diastereomer    thereof.

Another embodiment of present invention is that (xvi) particularcompounds of formula (I) are the following:

-   6-Amino-9-benzyl-2-(methylsulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-benzyl-2-(ethyl sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-benzyl-2-(2-methoxyethyl sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-benzyl-2-(propyl sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-benzyl-2-(butyl sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-benzyl-2-(3-methoxypropyl sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-benzyl-2-(2,2,2-trifluoroethyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-benzyl-2-(cyclohexylmethyl sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(4-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(4-methoxyphenyl)methyl]-2-(methylsulfonimidoyl)-7H-purin-8-one;-   6-Amino-2-(3-chloropropyl    sulfonimidoyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one;-   6-Amino-9-[(4-methoxyphenyl)methyl]-2-(3-pyrrolidin-1-ylpropylsulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(4-chlorophenyl)methyl]-2-(methyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(6-chloro-3-pyridyl)methyl]-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(2-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;-   6-Amino-2-(methylsulfonimidoyl)-9-(3-pyridylmethyl)-7H-purin-8-one;-   3-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzonitrile;-   3-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzamide;-   6-Amino-2-(methyl sulfonimidoyl)-9-(2-pyridylmethyl)-7H-purin-8-one;-   6-Amino-2-(methyl sulfonimidoyl)-9-(4-pyridylmethyl)-7H-purin-8-one;-   6-Amino-9-isobutyl-2-(propylsulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(3-chlorophenyl)methyl]-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-2-(propyl    sulfonimidoyl)-9-[[4-(trifluoromethyl)phenyl]methyl]-7H-purin-8-one;-   6-Amino-9-[(4-fluorophenyl)methyl]-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(4-bromophenyl)methyl]-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(3,4-dichlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-(3,4-difluorophenylmethyl)-2-(propylsulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(4-chloro-3-methyl-phenyl)methyl]-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-2-(propyl sulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one;-   6-Amino-9-[(4-chloro-3-fluorophenyl)methyl]-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(2,4-difluorophenyl)methyl]-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   4-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzonitrile;-   4-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzamide;-   6-Amino-9-[(6-methyl-3-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(2-methyl-4-pyridyl)methyl]-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(3-chloro-4-methyl-phenyl)methyl]-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(4-methyl sulfonylphenyl)methyl]-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   Methyl    4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzoate;-   4-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzoic    acid;-   4-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]-N-(2-methoxyethyl)benzamide;-   6-Amino-9-[[4-(piperidine-1-carbonyl)phenyl]methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;-   6-Amino-2-(S-propylsulfonimidoyl)-9-[[4-(pyrrolidine-1-carbonyl)phenyl]methyl]-7H-purin-8-one;-   6-Methyl-2-(propyl    sulfonimidoyl)-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one;-   6-Methyl-9-[(2-methylpyrimidin-5-yl)methyl]-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(4-chlorophenyl)methyl]-2-(ethyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-2-(ethyl sulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one;    and-   6-Amino-2-(ethyl    sulfonimidoyl)-9-[(4-fluorophenyl)methyl]-7H-purin-8-one;    or pharmaceutically acceptable salt, enantiomer or diastereomer    thereof.

Another embodiment of present invention is that (xvii) more particularcompounds of formula (I) are the following:

-   6-Amino-9-benzyl-2-(propylsulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(4-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(6-chloro-3-pyridyl)methyl]-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(4-fluorophenyl)methyl]-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(4-bromophenyl)methyl]-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-2-(propyl sulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one;-   6-Amino-9-[(6-methyl-3-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;-   Methyl    4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzoate;-   4-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzoic    acid;-   6-Methyl-9-[(2-methylpyrimidin-5-yl)methyl]-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   6-Amino-9-[(4-chlorophenyl)methyl]-2-(ethyl    sulfonimidoyl)-7H-purin-8-one; and-   6-Amino-2-(ethyl sulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one;    or pharmaceutically acceptable salt, enantiomer or diastereomer    thereof.

Another embodiment of present invention is that (xviii) the mostparticular compounds of formula (I) are the following:

-   6-Amino-9-[(4-chlorophenyl)methyl]-2-(ethyl    sulfonimidoyl)-7H-purin-8-one; and-   6-Amino-2-(ethyl sulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one;    or pharmaceutically acceptable salt, enantiomer or diastereomer    thereof.

Another embodiment of present invention is (xix) a compound of formula(Ia),

wherein

-   R⁴ is C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₇cylcoalkylC₁₋₆alkyl,    C₁₋₆alkoxyC₁₋₆alkyl or pyrrolidinylC₁₋₆alkyl;-   R⁵ is C₁₋₆alkyl, phenylC₁₋₆alkyl, pyridinylC₁₋₆alkyl or    pyrimidinylC₁₋₆alkyl, said phenylC₁₋₆alkyl, pyridinylC₁₋₆alkyl and    pyrimidinylC₁₋₆alkyl are unsubstituted or substituted by one, two or    three substituents independently selected from halogen, C₁₋₆alkyl,    C₁₋₆alkoxy, cyano, carboxy, carbamoyl, haloC₁₋₆alkyl,    C₁₋₆alkylsulfonyl, C₁₋₆alkoxycarbonyl,    C₁₋₆alkoxyC₁₋₆alkylaminocarbonyl, pyrrolidinylcarbonyl and    piperidinylcarbonyl;-   R⁶ is H or C₁₋₆alkyl-C(O)O—C₁₋₆alkyl-;-   R⁷ is H, C₁₋₆alkyl, C₃₋₇cycloalkyl or C₁₋₁₀alkylcarbonyl;-   R⁸ is H, C₁-6alkylcarbonyl, carboxyC₁₋₆alkylcarbonyl,    C₁-6alkyoxycarbonylC₁₋₆alkylcarbonyl or benzoyl;    provided that R⁶, R⁷ and R⁸ are not H simultaneously;    or pharmaceutically acceptable salt, enantiomer or diastereomer    thereof.

A further embodiment of present invention is (xx) a compound of formula(Ia), wherein

-   R⁴ is methyl, ethyl, propyl, butyl, chloropropyl, cyclohexylmethyl,    methoxyethyl, methoxypropyl, pyrrolidinylpropyl or trifluoroethyl;-   R⁵ is isobutyl, benzyl, chlorobenzyl, fluorobenzyl, bromobenzyl,    chlorofluorobenzyl, chloromethylbenzyl, dichlorobenzyl,    difluorobenzyl, methylbenzyl, methoxybenzyl, cyanobenzyl,    carbamoylbenzyl, trifluoromethylbenzyl, methyl sulfonylbenzyl,    methoxycarbonylbenzyl, carboxybenzyl,    methoxyethylaminocarbonylbenzyl, piperidinylcarbonylbenzyl,    pyrrolidinylcarbonylbenzyl, pyridinylmethyl, chloropyridinylmethyl,    methylpyridinylmethyl, pyrimidinylmethyl or methylpyrimidinylmethyl;-   R⁶ is H, acetoxymethyl, acetoxyethyl or dimethylpropanoyloxymethyl;-   R⁷ is H, ethyl, propyl, isopropyl, cyclopropyl, acetyl, pentanoyl,    methylpentanoyl, propylpentanoyl, ethylbutanoyl, methylbutanoyl or    dimethylpropanoyl;-   R⁸ is H, acetyl, pentanoyl, carboxypropanoyl,    ethoxycarbonylpropanoyl or benzoyl;    provided that R⁶, R⁷ and R⁸ are not H simultaneously;    or pharmaceutically acceptable salt, enantiomer or diastereomer    thereof.

A further embodiment of present invention is (xxi) a compound of formula(Ia), wherein R⁴ is C₁₋₆alkyl; or pharmaceutically acceptable salt,enantiomer or diastereomer thereof.

A further embodiment of present invention is (xxii) a compound offormula (Ia), wherein R⁴ is methyl or propyl; or pharmaceuticallyacceptable salt, enantiomer or diastereomer thereof.

A further embodiment of present invention is (xxiii) a compound offormula (Ia), wherein R⁵ is phenylC₁₋₆alkyl or pyridinylC₁₋₆alkyl, saidphenylC₁₋₆alkyl and pyridinylC₁₋₆alkyl are unsubstituted or substitutedby one to three substituents independently selected from halogen orC₁₋₆alkyl; or pharmaceutically acceptable salt, enantiomer ordiastereomer thereof.

A further embodiment of present invention is a compound of formula (Ia),wherein R⁵ is benzyl, methylbenzyl, chlorobenzyl ormethylpyridinylmethyl; or pharmaceutically acceptable salt, enantiomeror diastereomer thereof.

A further embodiment of present invention is (xxiv) a compound offormula (Ia), wherein R⁵ is benzyl, chlorobenzyl ormethylpyridinylmethyl; or pharmaceutically acceptable salt, enantiomeror diastereomer thereof.

A further embodiment of present invention is (xxv) a compound of formula(Ia), wherein R⁷ is H, C₁₋₆alkyl or C₁₋₁₀alkylcarbonyl; orpharmaceutically acceptable salt, enantiomer or diastereomer thereof.

A further embodiment of present invention is (xxvi) a compound offormula (Ia), wherein R⁷ is H, ethyl, propyl, methylpentanoyl orpropylpentanoyl; or pharmaceutically acceptable salt, enantiomer ordiastereomer thereof.

A further embodiment of present invention is (xxvii) a compound offormula (Ia), wherein R⁸ is H, C₁₋₆alkylcarbonyl orcarboxyC₁₋₆alkylcarbonyl; or pharmaceutically acceptable salt,enantiomer or diastereomer thereof.

A further embodiment of present invention is (xxviii) a compound offormula (Ia), wherein R⁸ is H, pentanoyl or carboxypropanoyl; orpharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment of present invention is that (xix) particularcompounds of formula (Ia) are the following:

-   N-[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]pentanamide;-   N-[[6-Amino-9-[(4-chlorophenyl)methyl]-8-oxo-7H-purin-2-yl]-oxo-propyl-λ⁴-sulfanylidene]acetamide;-   N-[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-methyl-oxo-λ⁴-sulfanylidene]acetamide;-   4-[[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]amino]-4-oxo-butanoic    acid;-   4-[[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]amino]-4-oxo-butanoic    acid;-   4-[[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]amino]-4-oxo-butanoic    acid;-   Ethyl    4-[[(6-amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]amino]-3-oxo-butanoate;-   Ethyl    4-[[(6-amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]amino]-4-oxo-butanoate;-   N-[(6-amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]benzamide;-   N-[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]benzamide;-   9-Benzyl-6-(ethylamino)-2-(propyl sulfonimidoyl)-7H-purin-8-one;-   6-(Ethylamino)-9-[(6-methyl-3-pyridyl)methyl]-2-(S-propyl    sulfonimidoyl)-7H-purin-8-one;-   9-[(4-Chlorophenyl)meth thy]-6-(ethylamino)-2-(propyl    sulfonimidoyl)-7H-purin-8-one;-   9-Benzyl-6-(propylamino)-2-(propyl sulfonimidoyl)-7H-purin-8-one;-   9-Benzyl-6-(isopropylamino)-2-(propyl sulfonimidoyl)-7H-purin-8-one;-   9-Benzyl-6-(cyclopropylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one;-   N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-propyl-pentanamide;-   N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]acetamide;-   N-[9-Benzyl-8-oxo-2-(propyl    sulfonimidoyl)-7H-purin-6-yl]pentanamide;-   N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-ethyl-butanamide;-   N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propyl    sulfonimidoyl)-7H-purin-6-yl]-3-methyl-butanamide;-   N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-methyl-pentanamide;-   N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2,2-dimethyl-propanamide;-   N-[9-Benzyl-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-propyl-pentanamide;-   [6-Amino-9-benzyl-2-(methyl sulfonimidoyl)-8-oxo-purin-7-yl]methyl    acetate;-   [6-Amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purin-7-yl]methyl    acetate;-   [6-Amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purin-7-yl]methyl    2,2-dimethylpropanoate; and    1-[6-Amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purin-7-yl]ethyl    acetate;    or pharmaceutically acceptable salt, enantiomer or diastereomer    thereof.

In some embodiments, compounds of present invention were tested andcompared with the following reference compounds:

Compound P-2 and P-5 were disclosed in WO2006117670 as example 2 and 5respectively, compound GS-9620 was disclosed in US20100143301 as example49, compound S-1 was disclosed in JP1999193282.

Synthesis

The compounds of the present invention can be prepared by anyconventional means. Suitable processes for synthesizing these compoundsas well as their starting materials are provided in the schemes belowand in the examples. All substituents, in particular, R¹ to R″ are asdefined above unless otherwise indicated. Furthermore, and unlessexplicitly otherwise stated, all reactions, reaction conditions,abbreviations and symbols have the meanings well known to a person ofordinary skill in organic chemistry.

A compound of formula VI is prepared by cyclization of isocyanate VIIwith aminomalononitrile-p-toluenesulfonate. Then bicycle IV issynthesized by reaction of compound of formula VI with benzoylisothiocyanate with inorganic base, such as sodium hydroxide orpotassium hydroxide. Alkylation of bicycle IV with alkylhalide V in thepresence of base such as K₂CO₃, NaH or Cs₂CO₃, gives compound of formulaIIIa. Then compound of formula IIa is prepared by oxidation of compoundof formula IIIa with an oxidant, such as meta-chloroperoxybenzoic acid,urea-hydrogen peroxide adduct or HIO₄. Compound of formula Ie isobtained by imination of compound of formula IIa with imination reagent,such as sodium azide in acid, said acid is for example Eaton's reagentor PPA.

-   -   R^(a) is R¹ or R⁴, R^(b) is R² or R⁵, R⁷ is C₁₋₆alkyl,        C₃₋₇cycloalkyl or PMB, R¹² is C₁₋₁₀alkyl.

A compound of formula X is prepared by reaction of compound of formulaXI with R^(b)NH₂. Reduction of compound X gives the compound of formulaIX. Cyclization of compound of formula IX with cyclization reagents,such as phosgene, carbonyl diimidazole, diethyl carbonate or triphosgeneaffords compound of formula VIII. A compound of formula IIIb is preparedby treating the compound of formula VIII with R⁷NH₂ upon heating. Acompound of formula Ie is prepared by deprotection of compound offormula IIIb while R⁷ is PMB with acid, such as CF₃COOH, followed byoxidation with an oxidant, such as meta-chloroperoxybenzoic acid,urea-hydrogen peroxide adduct or HIO₄, and imination with iminationreagent, such as sodium azide in acid, said acid is for example Eaton'sreagent or PPA. A compound of formula Ic is obtained by direct oxidationof compound of formula IIIb to give compound IIb while R⁷ is alkyl orcycloalkyl, followed by imination with imination reagent, such as sodiumazide in acid, said acid is for example Eaton's reagent or PPA. Acompound of formula Id is obtained by acylation of compound of formulaIIIa to give compound IIIc, followed by oxidation with an oxidant, suchas meta-chloroperoxybenzoic acid, urea-hydrogen peroxide adduct or HIO₄,and imination with imination reagent, such as sodium azide in acid, saidacid is for example Eaton's reagent or PPA.

R^(a) is R¹, R⁴ or R⁹; R^(b) is R², R⁵ or R¹⁰.

Prodrugs of formula XIII or XIV can be prepared according Scheme 3.

Compound of formula XIII is synthesized by alkylation of active parentcompounds of formula Ie with haloester, such as chloromethyl acetate.Compound of formula XIV is synthesized by reaction of active parentcompound of formula Ie with carboxylic anhydride, such as aceticanhydride, or acylchloride, such as 4-chloro-4-oxo-butanoate.

This invention also relates to a process for the preparation of acompound of formula (I) or (Ia) comprising the reaction of:

(a) the reaction of a compound of formula (IIa),

with an imination reagent;(b) the reaction of a compound of formula (IIb),

with an imination reagent; wherein R^(a) is R¹ or R⁴, R^(b) is R² or R⁵,R⁷ is C₁₋₆alkyl or C₃₋₇cycloalkyl;(c) the reaction of a compound of formula (IIIc),

with an oxidant followed by an imination reagent, wherein R^(a) is R¹ orR⁴, R^(b) is R² or R⁵, R¹² is C₁₋₁₀alkyl;(d) the reaction of a compound of formula (IIIa),

with an oxidant followed by an imination reagent, wherein R^(a) is R¹ orR⁴, R^(b) is R² or R⁵;(e) the reaction of a compound of formula (Ie),

with haloester;(f) the reaction of a compound of formula (Ie),

with carboxylic anhydride or acylchloride;or wherein R^(a), R^(b), R¹, R², R⁴, R⁵, R⁷ and R¹² are defined above.

In step (a), (b), (c) and (d), the imination reagent can be for examplesodium azide in acid, said acid can be for example Eaton's reagent orPPA.

In step (c) and (d), the oxidant can be for examplemeta-chloroperoxybenzoic acid, urea-hydrogen peroxide adduct or HIO₄.

In step (e), the haloester can be for example chloromethyl acetate.

In step (f), the carboxylic anhydride can be for example aceticanhydride; the acylchloride can be 4-chloro-4-oxo-butanoate.

A compound of formula (I) and (Ia) when manufactured according to theabove process is also an object of the invention.

Pharmaceutical Compositions and Administration

Another embodiment provides pharmaceutical compositions or medicamentscontaining the compounds of the invention and a therapeutically inertcarrier, diluent or excipient, as well as methods of using the compoundsof the invention to prepare such compositions and medicaments. In oneexample, compounds of formula (I) or their prodrugs may be formulated bymixing at ambient temperature at the appropriate pH, and at the desireddegree of purity, with physiologically acceptable carriers, i.e.,carriers that are non-toxic to recipients at the dosages andconcentrations employed into a galenical administration form. The pH ofthe formulation depends mainly on the particular use and theconcentration of compound, but preferably ranges anywhere from about 3to about 8. In one example, a compound of formula (I) or their prodrugsare formulated in an acetate buffer, at pH 5. In another embodiment, thecompounds of formula (I) or their prodrugs are sterile. The compound maybe stored, for example, as a solid or amorphous composition, as alyophilized formulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. The “effective amount” of the compoundto be administered will be governed by such considerations, and is theminimum amount necessary to activate TLR7 receptor and lead to produceINF-α and other cytokines, which can be used, but not limited, for thetreatment or prevention of hepatitis B and/or C viral infected patients.

In one example, the pharmaceutically effective amount of the compound ofthe invention administered parenterally per dose will be in the range ofabout 0.1 to 50 mg/kg, alternatively about 0.1 to 30 mg/kg of patientbody weight per day, with the typical initial range of compound usedbeing 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosageforms, such as tablets and capsules, preferably contain from about 20 toabout 1000 mg of the compound of the invention.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier or excipient. Suitable carriers and excipientsare well known to those skilled in the art and are described in detailin, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Formsand Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice ofPharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,Raymond C. Handbook of Pharmaceutical Excipients. Chicago,Pharmaceutical Press, 2005. The formulations may also include one ormore buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents, diluents and other knownadditives to provide an elegant presentation of the drug (i.e., acompound of the present invention or pharmaceutical composition thereof)or aid in the manufacturing of the pharmaceutical product (i.e.,medicament).

An example of a suitable oral dosage form is a tablet containing about20 to 1000 mg of the compound of the invention compounded with about 30to 90 mg anhydrous lactose, about 5 to 40 mg sodium croscarmellose,about 5 to 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mgmagnesium stearate. The powdered ingredients are first mixed togetherand then mixed with a solution of the PVP. The resulting composition canbe dried, granulated, mixed with the magnesium stearate and compressedto tablet form using conventional equipment. An example of an aerosolformulation can be prepared by dissolving the compound, for example 20to 1000 mg, of the invention in a suitable buffer solution, e.g. aphosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride,if desired. The solution may be filtered, e.g., using a 0.2 micronfilter, to remove impurities and contaminants.

An embodiment, therefore, includes a pharmaceutical compositioncomprising a compound of formula (I) or its prodrugs, formula (Ia), orpharmaceutically acceptable salts or enantiomers or diastereomersthereof.

In a further embodiment includes a pharmaceutical composition comprisinga compound of formula (I) or its prodrugs, formula (Ia), orpharmaceutically acceptable salts or enantiomers or diastereomersthereof, together with a pharmaceutically acceptable carrier orexcipient.

Another embodiment includes a pharmaceutical composition comprising acompound of formula (I) or its prodrugs, formula (Ia), orpharmaceutically acceptable salts or enantiomers or diastereomersthereof for use in the treatment of hepatitis B virus infection.

Indications and Methods of Treatment

The present invention provides methods for treating or preventing ahepatitis B viral infection and/or hepatitis C viral infection in apatient in need thereof.

The present invention further provides methods for introducing atherapeutically effective amount of a compound of formula (I) or itsprodrugs, or other compounds of the invention into the blood stream of apatient for the treatment and/or prevention of hepatitis B and/or Cviral infection.

The methods of the present invention are particularly well suited forhuman patients. In particular, the methods and doses of the presentinvention can be useful for, but not limited to, HBV and/or HCV infectedpatients. The methods and doses of the present invention are also usefulfor patients undergoing other antiviral treatments. The preventionmethods of the present invention are particularly useful for patients atrisk of viral infection. These patients include, but are not limited tohealth care workers, e.g., doctors, nurses, hospice care givers;military personnel; teachers; childcare workers; patients traveling to,or living in, foreign locales, in particular third world localesincluding social aid workers, missionaries, and foreign diplomats.Finally, the methods and compositions include the treatment ofrefractory patients or patients resistant to treatment such asresistance to reverse transcriptase inhibitors, protease inhibitors,etc.

Another embodiment includes a method of treating or preventing hepatitisB viral infection and/or hepatitis C viral infection in a mammal in needof such treatment, wherein the method comprises administering to saidmammal a therapeutically effective amount of a compound of formula (I),or enantiomers, diastereomers, prodrugs or pharmaceutically acceptablesalts thereof.

EXAMPLES

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention.

Abbreviations

-   -   aq. aqueous    -   BSA: N, O-bis(trimethylsilyl)acetamide    -   CDCl₃: deuterated chloroform    -   CD₃OD: deuterated methanol    -   CDI: N,N′-carbonyl diimidazole    -   DIEPA: N,N-diethylpropylamine    -   DMF: dimethyl formamide    -   DMSO: dimethyl sulfoxide    -   DBU: 1,8-Diazabicycloundec-7-ene    -   DPPA: diphenylphosphoryl azide    -   EC₅₀: the molar concentration of an agonist, which produces 50%        of the maximum possible response for that agonist.    -   EDC:        N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine        EtOAc or EA: ethyl acetate    -   HATU:        (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate)    -   hr(s): hour(s)    -   HPLC: high performance liquid chromatography    -   HOBt: t-hydroxybenzotriazole    -   MS (ESI): mass spectroscopy (electron spray ionization)    -   m-CPBA: 3-chloroperbenzoic acid    -   min(s) minute(s)    -   MTEB: methyl tert-butyl ether    -   NMR: nuclear magnetic resonance    -   NMP: N-methylpyrrolidone    -   obsd. observed    -   PE: petroleum ether    -   PMB: p-methoxybenzyl    -   PPA: polyphosphoric acid    -   RT or rt: room temperature    -   sat. saturated    -   TFA: trifluoroacetic acid    -   THF: tetrahydrofuran    -   TEA: triethylamine    -   V/V volume ratio

General Experimental Conditions

Intermediates and final compounds were purified by flash chromatographyusing one of the following instruments: i) Biotage SP1 system and theQuad 12/25 Cartridge module. ii) ISCO combi-flash chromatographyinstrument. Silica gel Brand and pore size: i) KP-SIL 60 Å, particlesize: 40-60 μm; ii) CAS registry NO: Silica Gel: 63231-67-4, particlesize: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang ChemicalCo., Ltd, pore: 200-300 or 300-400.

Intermediates and final compounds were purified by preparative HPLC onreversed phase column using X Bridge™ Perp C₁₈ (5 μm, OBD™ 30×100 mm)column or SunFire™ Perp C₁₈ (5 μm, OBD™ 30×100 mm) column.

LC/MS spectra were obtained using a Waters UPLC-SQD Mass. Standard LC/MSconditions were as follows (running time 3 minutes):

Acidic condition: A: 0.1% formic acid and 1% acetonitrile in H₂O; B:0.1% formic acid in acetonitrile;

Basic condition: A: 0.05% NH₃—H₂O in H₂O; B: acetonitrile.

Mass spectra (MS): generally only ions which indicate the parent massare reported, and unless otherwise stated the mass ion quoted is thepositive mass ion (M+H)⁺.

NMR Spectra were obtained using Bruker Avance 400 MHz.

All reactions involving air-sensitive reagents were performed under anargon atmosphere. Reagents were used as received from commercialsuppliers without further purification unless otherwise noted.

PREPARATIVE EXAMPLES Example 16-Amino-9-benzyl-2-(methylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of4-amino-3-benzyl-2-oxo-1H-imidazole-5-carbonitrile

To a solution of aminomalononitrile-p-toluenesulfonate (25 g, 98.5 mmol,TCI, Catalog number: A1119-25G) in dry THF (100 mL) was added benzylisocyanate (13.2 g, 98.5 mmol) and TEA (10.2 g, 79.0 mmol) at RT. Afterstirred at rt for 24 hrs, the reaction was concentrated in vacuo and theresidue partitioned between EtOAc (500 mL) and water (250 mL). Theseparated organic layer was washed with brine (50 mL) two times, andextracted with sodium hydroxide solution (50 mL, 1N) two times. Thecombined sodium hydroxide solution layer was neutralized with 10 wt. %sodium hydrogen sulfate solution and extracted with EtOAc. The separatedorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was triturated in2-isopropoxypropane and then the suspension was filtered to give4-amino-3-benzyl-2-oxo-1H-imidazole-5-carbonitrile (compound 1a) as ayellow solid (15 g), the product was used in the next step withoutfurther purification. MS obsd. (ESI⁺) [(M+H)⁺]: 215.

Step 2: Preparation of 6-amino-9-benzyl-2-sulfanyl-7H-purin-8-one

To a solution of 4-amino-3-benzyl-2-oxo-1H-imidazole-5-carbonitrile(15.0 g, 70.0 mmol, compound 1a) in THF (700 mL) was addedbenzoylisothiocyanate (28.6 g, 175.1 mmol, TCI, Catalog number:A11596-100G) dropwise. After stirred at RT for 12 hrs, the reactionmixture was concentrated in vacuo. The residue was triturated in diethylether (100 mL) and the resulting precipitate was collected byfiltration.

To a solution of the obtained precipitate in THF (700 mL) was addedsodium hydroxide (70 mL, 2 N). The mixture was refluxed for 50 hrs, andthen acidified to pH3 with 10% wt. aqueous sodium hydrogen sulfatesolution. The resulting precipitate was collected by filtration to givea crude product 6-amino-9-benzyl-2-sulfanyl-7H-purin-8-one (8.1 g,compound 1b) as a yellow solid. The product was used in the next stepwithout further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 274.

Step 3: Preparation of 6-amino-9-benzyl-2-methylsulfanyl-7H-purin-8-one

To a solution of 6-amino-9-benzyl-2-sulfanyl-7H-purin-8-one (5.46 g,20.0 mmol, compound 1b) in DMF was added potassium carbonate (2.76 g,20.0 mmol). And then methyl iodide (2.84 g, 20.0 mmol) in DMF (5.0 mL)was slowly added to previous solution. After stirred at RT for 12 hrs,the reaction mixture was poured into water (200 mL), then acidified with10 wt. % aqueous sodium hydrogen sulfate solution and extracted withEtOAc (100 mL) two times. The organic layer was washed with brine, driedand concentrated in vacuo to give the crude product, which was purifiedby flash chromatography on silica gel to give6-amino-9-benzyl-2-methylsulfanyl-7H-purin-8-one (4.9 g, compound 1c) asa white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 288.

Step 4: Preparation of 6-amino-9-benzyl-2-methylsulfinyl-7H-purin-8-one

To a suspension of compound6-amino-9-benzyl-2-methylsulfanyl-7H-purin-8-one (2.5 g, 8.7 mmol,compound 1c) in DCM/MeOH (500 mL, V/V=1:1) was added 3-chloroperbenzoicacid (2.15 g, 8.7 mmol, 70% purity, Aldrich, Catalog number:273031-100G). After reaction was stirred for 2 hrs, the volume ofreaction mixture was reduced in vacuo to about 50 mL. The resultingprecipitate was collected by filtration, washed with methanol and driedto give 6-amino-9-benzyl-2-methylsulfinyl-7H-purin-8-one (1.0 g,compound 1d) as a white solid. The product was used in the next stepwithout further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 304.

Step 5: Preparation of6-amino-9-benzyl-2-(methylsulfonimidoyl)-7H-purin-8-one

To a solution of 6-amino-9-benzyl-2-methylsulfinyl-7H-purin-8-one (1.4g, 4.6 mmol, compound 1d) in Eaton's reagent (40 mL, phosphoruspentoxide, 7.5 wt. % in methanesulphonic acid, Aldrich, Catalog number:380814-100ML) was added sodium azide (360 mg, 5.5 mmol) at 50° C. Afterbeing stirred at this temperature for 30 minutes, the reaction mixturewas cooled to RT and poured into sat. aqueous sodium bicarbonatesolution. The reaction mixture was extracted with n-BuOH (100 mL) twotimes, and the organic phase was concentrated in vacuo. The residue wassubmitted for purification by HPLC to give 6-amino-9-benzyl-2-(methylsulfonimidoyl)-7H-purin-8-one (900 mg, compound 1) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 10.6 (br. s, 1H), 7.26-7.34 (m, 5H), 7.07(br. s., 2H), 4.96 (s, 2H), 4.04 (s, 1H), 3.18 (s, 3H). MS obsd. (ESI⁺)[(M⁺H)⁺]: 319.

Separation of compound of Example 1 by chiral HPLC afforded Example 1-A(faster eluting, 7.1 mg) and Example 1-B (slower eluting, 9.1 mg) aswhite solid. (Separation condition: methanol 5%-40% (0.05% DEA)/CO₂ onChiralPak OJ-3 column.)

Example 1-A

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.06 (br. s., 1H), 7.27-7.36 (m, 5H),6.98 (br. s., 2H), 4.97 (s, 2H), 4.06 (br. s., 1H), 3.18 (s, 3H). MSobsd. (ESI⁺) [(M+H)⁺]: 319.

Example 1-B

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.06 (br. s., 1H), 7.26-7.36 (m, 5H),6.98 (br. s., 2H), 4.96 (s, 2H), 4.07 (br. s., 1H), 3.18 (s, 3H). MSobsd. (ESI⁺) [(M+H)⁺]: 319.

Example 2 6-Amino-9-benzyl-2-(ethylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of 6-amino-9-benzyl-2-ethylsulfanyl-7H-purin-8-one

Compound 2a was prepared in analogy to Example 1, Step 3 by using ethylbromide instead of methyl iodide.6-Amino-9-benzyl-2-ethylsulfanyl-7H-purin-8-one (500 mg, compound 2a)was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 302.

Step 2: Preparation of 6-amino-9-benzyl-2-methylsulfinyl-7H-purin-8-one

Compound 2b was prepared in analogy to Example 1, Step 4 by using6-amino-9-benzyl-2-ethyl sulfanyl-7H-purin-8-one (compound 2a) insteadof 6-amino-9-benzyl-2-methyl sulfanyl-7H-purin-8-one (compound 1c).6-Amino-9-benzyl-2-ethyl sulfinyl-7H-purin-8-one (300 mg, compound 2b)was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 318.

Step 3: Preparation of6-amino-9-benzyl-2-(ethylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 1, Step 5 by using6-amino-9-benzyl-2-ethyl sulfinyl-7H-purin-8-one (compound 2b) insteadof 6-amino-9-benzyl-2-methyl sulfinyl-7H-purin-8-one (compound 1d).6-Amino-9-benzyl-2-(ethylsulfonimidoyl)-7H-purin-8-one (12 mg, compound2) was obtained as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm: 7.43(d, J=7.03 Hz, 2H), 7.27-7.36 (m, 3H), 5.11 (s, 2H), 3.44-3.62 (m, 2H),1.30 (t, J=7.40 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 333.

Example 36-Amino-9-benzyl-2-(2-methoxyethylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-amino-9-benzyl-2-(2-methoxyethylsulfanyl)-7H-purin-8-one

Compound 3a was prepared in analogy to Example 1, Step 3 by using2-bromoethyl methyl ether (TCI, Catalog number: B1242-250G) instead ofmethyl iodide.6-Amino-9-benzyl-2-(2-methoxyethylsulfanyl)-7H-purin-8-one (600 mg,compound 3a) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:332.

Step 2: Preparation of6-amino-9-benzyl-2-(2-methoxyethylsulfinyl)-7H-purin-8-one

Compound 3b was prepared in analogy to Example 1, Step 4 by using6-amino-9-benzyl-2-(2-methoxyethyl sulfanyl)-7H-purin-8-one (compound3a) instead of 6-amino-9-benzyl-2-methyl sulfanyl-7H-purin-8-one(compound 1c).6-Amino-9-benzyl-2-(2-methoxyethylsulfinyl)-7H-purin-8-one (350 mg,compound 3b) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:348.

Step 3: Preparation of6-amino-9-benzyl-2-(2-methoxyethylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 1, Step 5 by using6-amino-9-benzyl-2-methoxyethyl sulfinyl-7H-purin-8-one (compound 3b)instead of 6-amino-9-benzyl-2-methyl sulfinyl-7H-purin-8-one (compound1d). 6-amino-9-benzyl-2-(2-methoxyethylsulfonimidoyl)-7H-purin-8-one (21mg, Example 3) was obtained as a white solid. ¹H NMR (400 MHz, CD₃OD) δppm: 7.44 (d, J=7.15 Hz, 2H), 7.25-7.36 (m, 3H), 5.12 (s, 2H), 3.75-3.82(m, 4H), 3.17 (s, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 363.

Separation of compound of Example 3 by chiral HPLC afforded Example 3-A(faster eluting, 7.0 mg) and Example 3-B (slower eluting, 5.0 mg) aswhite solid. (Separation condition: methanol 5%-40% (0.05% DEA)/CO₂ onChiralPak AS-3 column.)

Example 3-A

¹H NMR (400 MHz, CD₃OD) δ ppm: 7.43 (d, J=7.15 Hz, 2H), 7.25-7.36 (m,3H), 5.12 (s, 2H), 3.75-3.82 (m, 4H), 3.17 (s, 3H). MS obsd. (ESI⁺)[(M+H)⁺]: 363.

Example 3-B

¹H NMR (400 MHz, CD₃OD) δ ppm: 7.44 (d, J=7.15 Hz, 2H), 7.24-7.35 (m,3H), 5.12 (s, 2H), 3.75-3.82 (m, 4H), 3.17 (s, 3H). MS obsd. (ESI⁺)[(M+H)⁺]: 363.

Example 4 6-Amino-9-benzyl-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-amino-9-benzyl-2-(2-propylsulfanyl)-7H-purin-8-one

Compound 4a was prepared in analogy to Example 1, Step 3 by using1-bromopropane (TCI, Catalog number: B0638-500G) instead of methyliodide. 6-Amino-9-benzyl-2-propylsulfanyl-7H-purin-8-one (240 mg,compound 4a) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:316.

Step 2: Preparation of 6-amino-9-benzyl-2-propylsulfinyl-7H-purin-8-one

Compound 4b was prepared in analogy to Example 1, Step 4 by using6-amino-9-benzyl-2-propylsulfanyl-7H-purin-8-one (compound 4a) insteadof 6-amino-9-benzyl-2-methylsulfanyl-7H-purin-8-one (compound 1c).6-Amino-9-benzyl-2-(2-propyl sulfinyl)-7H-purin-8-one (210 mg, compound4b) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 332.

Step 3: Preparation of6-amino-9-benzyl-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 1, Step 5 by using6-amino-9-benzyl-2-(2-propyl sulfinyl)-7H-purin-8-one (compound 4b)instead of 6-amino-9-benzyl-2-(2-methyl sulfinyl)-7H-purin-8-one(compound 1d). 6-Amino-9-benzyl-2-(propylsulfonimidoyl)-7H-purin-8-one(80 mg, Example 4) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 10.65 (br. s., 1H), 7.26-7.37 (m, 5H), 6.98 (br. s.,2H), 4.97 (s, 2H), 4.02 (s, 1H), 3.33 (t, J=7.53 Hz, 2H), 1.55-1.74 (m,2H), 0.92 (t, J=7.53 Hz, 3H) MS obsd. (ESI⁺) [(M+H)⁺]: 347.

Separation of compound of Example 4 by chiral HPLC afforded Example 4-A(slower eluting, 500 mg) and Example 4-B (faster eluting, 490 mg) aswhite solid. (Separation condition: methanol 5%-40% (0.05% DEA)/CO₂ onChiralPak AS-3 column.)

Example 4-A

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.52 (br. s., 1H), 7.25-7.41 (m, 5H),6.96 (br. s., 2H), 4.96 (s, 2H), 4.03 (s, 1H), 3.24-3.42 (m, 2H),1.52-1.75 (m, 2H), 0.92 (t, J=7.53 Hz, 3H).

Example 4-B

¹H NMR (400 MHz, DMSO-d₆) δΔppm: 10.01 (br. s., 1H), 7.26-7.36 (m, 5H),6.97 (br. s., 2H), 4.96 (s, 2H), 4.03 (s, 1H), 3.26-3.41 (m, 2H),1.56-1.73 (m, 2H), 0.92 (t, J=7.53 Hz, 3H).

Example 5 6-Amino-9-benzyl-2-(butylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of 6-amino-9-benzyl-2-butylsulfanyl-7H-purin-8-one

Compound 5a was prepared in analogy to Example 1, Step 3 by using1-bromobutane (TCI, Catalog number: B560-500G) instead of methyl iodide.6-Amino-9-benzyl-2-butylsulfanyl-7H-purin-8-one (600 mg, compound 5a)was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 330.

Step 2: Preparation of 6-amino-9-benzyl-2-butylsulfinyl-7H-purin-8-one

Compound 5b was prepared in analogy to Example 1, Step 4 by using6-amino-9-benzyl-2-butyl sulfanyl-7H-purin-8-one (compound 5a) insteadof 6-amino-9-benzyl-2-methyl sulfanyl-7H-purin-8-one (compound 1c).6-Amino-9-benzyl-2-(2-butyl sulfinyl)-7H-purin-8-one (400 mg, compound5b) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 346.

Step 3: Preparation of6-amino-9-benzyl-2-(butylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 1, Step 5 by using6-amino-9-benzyl-2-(2-butyl sulfinyl)-7H-purin-8-one (compound 5b)instead of 6-amino-9-benzyl-2-(2-methyl sulfinyl)-7H-purin-8-one(compound 1d). 6-Amino-9-benzyl-2-(butylsulfonimidoyl)-7H-purin-8-one(40 mg, Example 5) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 10.59 (s, 1H), 7.24-7.39 (m, 5H), 6.97 (br. s., 2H),4.96 (s, 2H), 4.03 (s, 1H), 3.35-3.46 (m, 2H), 1.51-1.61 (m, 2H),1.27-1.39 (m, 2H), 0.84 (t, J=7.34 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]:361.

Example 66-Amino-9-benzyl-2-(3-methoxypropylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-amino-9-benzyl-2-(3-methoxypropylsulfanyl)-7H-purin-8-one

Compound 6a was prepared in analogy to Example 1, Step 3 by using1-bromo-3-methoxylpropane (TCI, Catalog number: B3499-25G) instead ofmethyl iodide. 6-Amino-9-benzyl-2-methoxypropylsulfanyl-7H-purin-8-one(220 mg, compound 6a) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 346.

Step 2: Preparation of6-amino-9-benzyl-2-(3-methoxypropylsulfinyl)-7H-purin-8-one

Compound 6b was prepared in analogy to Example 1, Step 4 by using6-amino-9-benzyl-2-propylsulfanyl-7H-purin-8-one (compound 6a) insteadof 6-amino-9-benzyl-2-methylsulfanyl-7H-purin-8-one (compound 1c).6-amino-9-benzyl-2-(2-methoxypropyl sulfinyl)-7H-purin-8-one (110 mg,compound 6b) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:362.

Step 3: Preparation of6-amino-9-benzyl-2-(butylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 1, Step 5 by using6-amino-9-benzyl-2-(2-methoxypropyl sulfinyl)-7H-purin-8-one (compound6b) instead of 6-amino-9-benzyl-2-(2-methyl sulfinyl)-7H-purin-8-one(compound 1d).6-Amino-9-benzyl-2-(methoxypropylsulfonimidoyl)-7H-purin-8-one (20 mg,Example 6) was obtained as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.59 (s, 1H), 7.29-7.34 (m, 5H), 7.00(br. s., 2H), 4.96 (s, 2H), 4.13 (s, 1H), 4.10 (m, 4H), 3.20 (s, 3H),1.86 (m, 2H). MS obsd. (ESI⁺) [(M+H)⁺]: 377.

Example 76-Amino-9-benzyl-2-(2,2,2-trifluoroethylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-amino-9-benzyl-2-(2,2,2-trifluoroethylsulfanyl)-7H-purin-8-one

Compound 7a was prepared in analogy to Example 1, Step 3 by using2,2,2-trifluoroethyl iodide (TCI, Catalog number: T1148-25G) instead ofmethyl iodide.6-Amino-9-benzyl-2-(2,2,2-trifluoroethyl)sulfanyl-7H-purin-8-one(compound 7a) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:356.

Step 2: Preparation of6-amino-9-benzyl-2-(2,2,2-trifluoroethylsulfinyl)-7H-purin-8-one

Compound 7b was prepared in analogy to Example 1, Step 4 by using6-amino-9-benzyl-2-2,2,2-trifluoroethylsulfanyl sulfanyl-7H-purin-8-one(compound 7a) instead of 6-amino-9-benzyl-2-methylsulfanyl-7H-purin-8-one (compound 1c).6-Amino-9-benzyl-2-(2-2,2,2-trifluoroethylsulfinyl)-7H-purin-8-one(compound 7b) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:372.

Step 3: Preparation of6-amino-9-benzyl-2-(2,2,2-trifluoroethylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 1, Step 5 by using6-amino-9-benzyl-2-(2-2,2,2-trifluoroethyl sulfinyl)-7H-purin-8-one(compound 7b) instead of 6-amino-9-benzyl-2-(2-methylsulfinyl)-7H-purin-8-one (compound 1d).6-Amino-9-benzyl-2-(2,2,2-trifluoroethylsulfonimidoyl)-7H-purin-8-one(20 mg, Example 7) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 10.59 (br. s., 1H), 7.25-7.37 (m, 5H), 7.06 (br. s.,2H), 4.95-5.01 (m, 3H), 4.85 (qd, J=10.02, 15.37 Hz, 1H), 4.63 (qd,J=9.92, 15.40 Hz, 1H). MS obsd. (ESI⁺) [(M+H)⁺]: 387.

Example 86-Amino-9-benzyl-2-(cyclohexylmethylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-amino-9-benzyl-2-(cyclohexylmethylsulfanyl)-7H-purin-8-one

Compound 8a was prepared in analogy to Example 1, Step 3 by usingcyclohexylmethyl bromide (TCI, Catalog number: B1708-25G) instead ofmethyl iodide.6-Amino-9-benzyl-2-cyclohexylmethylsulfanyl-7H-purin-8-one (260 mg.compound 8a) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:370.

Step 2: Preparation of6-amino-9-benzyl-2-(cyclohexylmethylsulfinyl)-7H-purin-8-one

Compound 8b was prepared in analogy to Example 1, Step 4 by using6-amino-9-benzyl-2-cyclohexylmethyl sulfanyl-7H-purin-8-one (compound8a) instead of 6-amino-9-benzyl-2-methyl sulfanyl-7H-purin-8-one(compound 1c). 6-Amino-9-benzyl-2-(2-cyclohexylmethylsulfinyl)-7H-purin-8-one (120 mg, compound 8b) was obtained as a whitesolid. MS obsd. (ESI⁺) [(M+H)⁺]: 386.

Step 3: Preparation of6-amino-9-benzyl-2-(cyclohexylmethylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 1, Step 5 by using6-amino-9-benzyl-2-(2-cyclohexylmethyl sulfinyl)-7H-purin-8-one(compound 8b) instead of 6-amino-9-benzyl-2-methylsulfinyl-7H-purin-8-one (compound 1d).6-Amino-9-benzyl-2-(cyclohexylmethylsulfonimidoyl)-7H-purin-8-one (40mg, Example 8) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm: 10.59 (br. s., 1H), 7.27-7.33 (m, 5H), 6.97 (br. s., 2H), 4.97(s, 2H), 4.03 (s, 1H), 3.26-3.29 (m, 2H), 1.54-1.86 (m, 5H), 0.89-1.12(m, 6H). MS obsd. (ESI⁺) [(M+H)⁺]: 401.

Example 96-Amino-9-[(4-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of4-amino-3-[(4-chlorophenyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile

To a solution of triphosgene (5.9 g, 20 mmol) in dry THF (40 mL) wasadded (4-chlorophenyl)methylamine (8.5 g, 60 mmol, Accela ChemBio Inc,Catalog number: SY004062-25 g) and DIPEA (12.4 g, 96 mmol) in dry THF(80 mL) at −80° C. The solution was stirred at −80° C. for 15 min. Asolution of aminomalononitrile p-toluenesulfonate (15.2 g, 60 mmol, TCI,Catalog number: A1119-25G) and DIPEA (6.2 g, 48 mmol) in dry THF (40 mL)was added at −80° C. After stirred at RT for 24 hrs, the reaction wasconcentrated in vacuo and the residue was partitioned between EtOAc (300mL) and water (150 mL). The separated organic layer was washed withbrine (50 mL) two times, and extracted with sodium hydroxide solution(50 mL, 1 N) two times. The combined sodium hydroxide solution layer wasneutralized with 10% wt. sodium hydrogen sulfate solution and extractedwith EtOAc. Then the separated organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The residue was triturated with diethyl ether and then the mixture wasfiltered to give4-amino-3-[(4-chlorophenyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile(8.0 g, compound 9a) as a yellow solid. MS obsd. (ESI⁺) [(M+H)⁺]: 249.

Step 2: Preparation of6-amino-9-[(4-chlorophenyl)methyl]-2-sulfanyl-7H-purin-8-one

To a solution of4-amino-3-[(4-chlorophenyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile(8.0 g, 32.0 mmol, compound 9a) in THF (100 mL) was addedbenzoylisothiocyanate (11.5 g, 70.4 mmol, TCI, Catalog number:A11596-100G) dropwise. After stirred at RT for 12 hrs, the reactionmixture was concentrated in vacuo. The residue was triturated in diethylether (100 mL) and the resulting precipitate was collected byfiltration.

To a solution of the obtained precipitate in THF (300 mL) was addedsodium hydroxide (30 mL, 2 N). The mixture was refluxed for 50 hrs, andthen acidified to pH 3 with 10 wt. % aqueous sodium hydrogen sulfatesolution. The resulting precipitate was collected by filtration to givea crude product6-amino-9-[(4-chlorophenyl)methyl]-2-sulfanyl-7H-purin-8-one (compound9b) as a yellow solid (6.4 g). The product was used in the next stepwithout further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 308.

Step 3: Preparation of6-amino-9-[(4-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 9c was prepared in analogy to Example 1, Step 3 by usingn-propyl bromide and6-amino-9-[(4-chlorophenyl)methyl]-2-sulfanyl-7H-purin-8-one (compound9b) instead of methyl iodide and6-amino-9-phenylmethyl-2-sulfanyl-7H-purin-8-one (compound 1b).6-Amino-9-[(4-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (800mg, compound 9c) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 350.

Step 4: Preparation of6-amino-9-[(4-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one

Compound 9d was prepared in analogy to Example 1, Step 4 by using6-amino-9-[(4-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 9c) instead of 6-amino-9-benzyl-2-methylsulfanyl-7H-purin-8-one (compound 1c).6-Amino-9-[(4-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (150mg, compound 9d) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 366.

Step 5: Preparation of6-amino-9-[(4-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 1, Step 5 by using6-amino-9-[(4-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 9d) instead of 6-amino-9-benzyl-2-(2-methylsulfinyl)-7H-purin-8-one (compound 1d).6-Amino-9-[(4-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one(25 mg, Example 9) was obtained as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.60 (br. s, 1H), 7.32-7.42 (m, 4H),6.98 (br. s, 2H), 4.96 (s, 2H), 4.03 (s, 1H), 3.25-3.41 (m, 2H),1.56-1.68 (m, 2H), 0.91 (t, J=8 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 381.

Separation of compound of Example 9 by chiral HPLC afforded Example 9-A(faster eluting, 21 mg) and Example 9-B (slower eluting, 10 mg) as whitesolid. (Separation condition: methanol 5%-40% (0.05% DEA)/CO₂ onChiralPak OJ-3 column.)

Example 9-A

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.63 (br. s, 1H), 7.34-7.41 (m, 4H),6.99 (br. s, 2H), 4.96 (s, 2H), 4.05 (br. s, 1H), 3.29-3.38 (m, 2H),1.58-1.66 (m, 2H), 0.91 (t, J=8 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 381.

Example 9-B

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.63 (br. s, 1H), 7.34-7.41 (m, 4H),6.99 (br. s, 2H), 4.96 (s, 2H), 4.05 (br. s, 1H), 3.29-3.38 (m, 2H),1.58-1.66 (m, 2H), 0.91 (t, J=8 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 381.

Example 106-Amino-9-[(4-methoxyphenyl)methyl]-2-(methylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of4-amino-3-[(4-methoxyphenyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile

Compound 10a was prepared in analogy to Example 9, Step 1 by using(4-methoxyphenyl)methylamine instead of 4-chloropenylmethylamine.4-Amino-3-[(4-methoxyphenyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile(7.5 g, compound 10a) was prepared as a yellow solid. MS obsd. (ESI⁺)[(M+H)⁺]: 245.

Step 2: Preparation of6-amino-9-[(4-methoxyphenyl)methyl]-2-sulfanyl-7H-purin-8-one

Compound 10b was prepared in analogy to Example 9, Step 2 by using4-amino-3-[(4-methoxyphenyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile(compound 10a) instead of4-amino-3-[(4-chlorophenyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile(compound 9a).6-Amino-9-[(4-methoxyphenyl)methyl]-2-sulfanyl-7H-purin-8-one (11.4 g,compound 10b) was prepared as a yellow solid. MS obsd. (ESI⁺) [(M+H)⁺]:304.

Step 3: Preparation of6-amino-9-[(4-methoxyphenyl)methyl]-2-methylsulfanyl-7H-purin-8-one

Compound 10c was prepared in analogy to Example 1, Step 3 by using6-amino-9-[(4-methoxyphenyl)methyl]-2-sulfanyl-7H-purin-8-one (compound10b) instead of 6-amino-9-benzyl-2-sulfanyl-7H-purin-8-one (compound1b). 6-Amino-9-[(4-methoxyphenyl)methyl]-2-methylsulfanyl-7H-purin-8-one(2.3 g, compound 10c) was prepared as a yellow solid. MS obsd. (ESI⁺)[(M+H)⁺]: 318.

Step 4: Preparation of6-amino-9-[(4-methoxyphenyl)methyl]-2-methylsulfinyl-7H-purin-8-one

Compound 10d was prepared in analogy to Example 1, Step 4 by using6-amino-9-[(4-methoxyphenyl)methyl]-2-methylsulfanyl-7H-purin-8-one(compound 10c) instead of6-amino-9-benzyl-2-methylsulfanyl-7H-purin-8-one (compound 1c).6-Amino-9-[(4-methoxyphenyl)methyl]-2-methylsulfinyl-7H-purin-8-one (130mg, compound 10d) was prepared as a yellow solid. MS obsd. (ESI⁺)[(M+H)⁺]: 334.

Step 5: Preparation of6-amino-9-[(4-methoxyphenyl)methyl]-2-(methylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 1, Step 5 by using6-amino-9-[(4-methoxyphenyl)methyl]-2-methyl sulfinyl-7H-purin-8-one(compound 10d) instead of 6-amino-9-benzyl-2-methylsulfinyl-7H-purin-8-one (compound 1d).6-Amino-9-[(4-methoxyphenyl)methyl]-2-(methylsulfonimidoyl)-7H-purin-8-one(10 mg, Example 10) was prepared as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 10.53 (br. s, 1H), 7.32 (t, J=6.41 Hz, 2H), 6.95 (br. s,2H), 6.89 (t, J=6.38 Hz, 2H), 4.89 (s, 2H), 4.07 (s, 1H), 3.72 (s, 3H),3.21 (s, 3H). MS obsd. (ESI⁺) [(M⁺H)⁺]: 349.

Example 116-Amino-2-(3-chloropropylsulfonimidoyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one

Step 1: Preparation of6-amino-2-(3-chloropropylsulfanyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one

Compound 11a was prepared in analogy to Example 1, Step 3 by using1-bromo-3-chloro-propane and6-amino-9-[(4-methoxyphenyl)methyl]-2-sulfanyl-7H-purin-8-one (compound10b) instead of methyl iodide and6-amino-9-benzyl-2-sulfanyl-7H-purin-8-one (compound 1b).6-Amino-2-(3-chloropropylsulfanyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one (3.2 g, compound11a) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 380.

Step 2: Preparation of6-amino-2-(3-chloropropylsulfinyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one

Compound 11b was prepared in analogy to Example 1, Step 4 by using6-amino-2-(3-chloropropylsulfanyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one(compound 11a) instead of 6-amino-9-benzyl-2-methylsulfanyl-7H-purin-8-one (compound 1c).6-Amino-2-(3-chloropropylsulfinyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one(1.3 g, compound 1b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 396.

Step 3: Preparation of6-amino-2-(3-chloropropylsulfonimidoyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one

The title compound was prepared in analogy to Example 1, Step 5 by using6-amino-2-(3-chloropropylsulfinyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one(compound 11b) instead of 6-amino-9-benzyl-2-(2-methylsulfanyl)-7H-purin-8-one (compound 1d). 6-Amino-2-(3-chloropropylsulfonimidoyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one (40 mg,Example 11) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δppm: 10.53 (br. s, 1H), 7.32 (t, J=6.41 Hz, 2H), 6.95 (br. s, 2H), 6.89(t, J=6.38 Hz, 2H), 4.89 (s, 2H), 4.07 (s, 1H), 3.89 (m, 2H), 3.72 (s,3H), 3.52 (m, 2H), 2.13 (m, 2H). MS obsd. (ESI⁺) [(M+H)⁺]: 411.

Example 126-Amino-9-[(4-methoxyphenyl)methyl]-2-(3-pyrrolidin-1-ylpropylsulfonimidoyl)-7H-purin-8-one

To a solution of6-amino-2-(3-chloropropylsulfonimidoyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one(150 mg, compound 11) in DMSO (5 mL) was added pyrrolidine (0.9 mL, 11.0mmol) drop wise. The mixture was stirred at 80° C. for 2 hrs. Theresulting mixture was diluted with brine (60 mL), extracted with EtOAc(60 mL) three times. The organic layer was combined, washed with brine,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by prep-HPLC to give6-amino-9-[(4-methoxyphenyl)methyl]-2-(3-pyrrolidin-1-ylpropylsulfonimidoyl)-7H-purin-8-one(26 mg, Example 12) as a light brown solid. ¹H NMR (400 MHz, DMSO-d₆) δppm: 10.88 (br. s, 1H), 7.29 (t, J=6.41 Hz, 2H), 7.05 (br. s, 2H), 6.88(t, J=6.38 Hz, 2H), 4.88 (s, 2H), 3.72 (m, 4H), 2.52 (m, 4H), 2.45 (m,4H), 1.84 (m, 2H), 1.67 (m, 4H). MS obsd. (ESI⁺) [(M⁺H)⁺]: 446.

Example 136-Amino-9-[(4-chlorophenyl)methyl]-2-(methylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-amino-9-[(4-chlorophenyl)methyl]-2-methylsulfanyl-7H-purin-8-one

Compound 13a was prepared in analogy to Example 1, Step 3 by using6-amino-9-[(4-chlorophenyl)methyl]-2-sulfanyl-7H-purin-8-one (compound9b) instead of 6-amino-9-benzyl-2-sulfanyl-7H-purin-8-one (compound 1b).6-Amino-9-[(4-chlorophenyl)methyl]-2-methylsulfanyl-7H-purin-8-one (1.2g, compound 13a) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 322.

Step 2: Preparation of6-amino-9-[(4-chlorophenyl)methyl]-2-methylsulfinyl-7H-purin-8-one

Compound 13b was prepared in analogy to Example 1, Step 4 by using6-amino-9-[(4-chlorophenyl)methyl]-2-methyl sulfanyl-7H-purin-8-one(compound 13a) instead of 6-amino-9-benzyl-2-methylsulfanyl-7H-purin-8-one (compound 1c).6-Amino-9-[(4-chlorophenyl)methyl]-2-methylsulfanyl-7H-purin-8-one (148mg, compound 13b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 338.

Step 3: Preparation of6-amino-9-[(4-chlorophenyl)methyl]-2-(methylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 1, Step 5 by using6-amino-9-[(4-chlorophenyl)methyl]-2-methyl sulfanyl-7H-purin-8-one(compound 13b) instead of using 6-amino-9-benzyl-2-methylsulfanyl-7H-purin-8-one (compound 1d).6-Amino-9-[(4-chlorophenyl)methyl]-2-methylsulfinyl-7H-purin-8-one (7mg, Example 13) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm: 10.53 (br. s, 1H), 7.36-7.51 (m, 4H), 6.98 (br. s, 2H), 4.96 (s,2H), 4.07 (s, 1H), 3.18 (s, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 353.

Example 146-Amino-9-[(6-chloro-3-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of4-amino-3-[(6-chloro-3-pyridyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile

Compound 14a was prepared in analogy to Example 9, Step 1 by using(6-chloro-3-pyridyl)methanamine (Alfa Aesar (China) Co., Ltd., Catalognumber: L19283-25 g) instead of (4-chlorophenyl)methylamine.4-Amino-3-[(6-chloro-3-pyridyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile(7.8 g, compound 14a) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 250.

Step 2: Preparation of6-amino-9-[(6-chloro-3-pyridyl)methyl]-2-sulfanyl-7H-purin-8-one

Compound 14b was prepared in analogy to Example 9, Step 2 by using4-amino-3-[(6-chloro-3-pyridyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile(compound 14a) instead of4-amino-3-[(4-chlorophenyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile(compound 9a).6-Amino-9-[(6-chloro-3-pyridyl)methyl]-2-sulfanyl-7H-purin-8-one (1.1 g,compound 14b) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:309.

Step 3: Preparation of6-amino-9-[(6-chloro-3-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 14c was prepared in analogy to Example 1, Step 3 by using6-amino-9-[(6-chloro-3-pyridyl)methyl]-2-sulfanyl-7H-purin-8-one(compound 14b) instead of 6-amino-9-benzyl-2-sulfanyl-7H-purin-8-one(compound 1b).6-Amino-9-[(6-chloro-3-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one(750 mg, compound 14c) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 351.

Step 4: Preparation of6-amino-9-[(6-chloro-3-pyridyl)methyl]-2-propylsulfinyl-7H-purin-8-one

Compound 14d was prepared in analogy to Example 1, Step 4 by using6-amino-9-[(6-chloro-3-pyridyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(compound 14c) instead of 6-amino-9-benzyl-2-methylsulfanyl-7H-purin-8-one (compound 1c).6-Amino-9-[(6-chloro-3-pyridyl)methyl]-2-propylsulfinyl-7H-purin-8-one(750 mg, compound 14d). MS obsd. (ESI⁺) [(M+H)⁺]: 367.

Step 5: Preparation of6-amino-9-[(6-chloro-3-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 1, Step 5 by using6-amino-9-[(6-chloro-3-pyridyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(compound 14d) instead of 6-amino-9-benzyl-2-methylsulfinyl-7H-purin-8-one (compound 1d).6-Amino-9-[(6-chloro-3-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one(4 mg, Example 14) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 10.80 (br. s, 1H), 8.45 (d, J=2.4 Hz, 1H), 7.81 (dd,J=2.4, 8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.04 (br. s, 2H), 5.01 (s,2H), 4.06 (s, 1H), 3.24-3.43 (m, 2H), 1.53-1.73 (m, 2H), 0.92 (t, J=8.0Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 382.

Example 156-Amino-9-[(2-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

To a solution of 4, 6-dichloro-5-nitro-2-propylsulfanyl-pyrimidine (10g, 37.0 mmol, J & K scientific, Catalog number: J92_090911_25G) andDIPEA (5.8 g, 45 mmol) in THF (200 mL) was added a solution of(2-chlorophenyl)methylamine (5.5 g, 39 mmol) in THF (50 mL) at −78° C.After the addition, the mixture was stirred at this temperature for 2hrs. The resulting mixture was concentrated, extracted with EtOAc. Theorganic phase was washed with water, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography eluted with PE/EtOAc from 20/1 to 5/1 (V/V) togive 6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine (11 g, compound 15a) as a yellow solid. MSobsd. (ESI⁺) [(M+H)⁺]: 373.

Step 2: Preparation of6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

To a solution of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(11 g, 29.5 mmol, compound 15a) and HOAc (17.7 g, 295 mmol) in THF (400mL) at 0° C. was added Zn dust (9.5 g, 147 mmol) in small portions.After the addition, the mixture was stirred at this temperature for 12hrs and filtered. The filtrate was basified with NaHCO₃, extracted withDCM, dried over anhydrous sodium sulfate and concentrated in vacuo togive6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(9.0 g, compound 15b). MS obsd. (ESI⁺) [(M+H)⁺]: 343.

Step 3: Preparation of6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

To a solution of6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(9.0 g, 26.2 mmol, compound 15b) in THF (800 mg) was added CDI (21 g,131 mmol). The reaction was kept at 80° C. for 12 hrs. The reactionmixture was cooled to RT, and then concentrated in vacuo. The residuewas diluted with water (100 mL), extracted with EtOAc (125 mL) twotimes, dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was purified by column eluted with PE/EtOAc from 10/1 to 1:1(V/V) to give6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (9.5g, compound 15c) as a gray solid. MS obsd. (ESI⁺) [(M+H)⁺]: 369.

Step 4: Preparation of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one

To a solution of 6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (9.0 g, 26.2 mmol, compound 15c) in n-BuOH (200mL) was added PMBNH₂ (36 g, 262 mmol). The reaction was stirred at 130°C. for 12 hrs. The reaction mixture was cooled to 20° C., poured intoPE. The formed precipitate was collected by filtration to give9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one as a white solid (10.2 g, compound 15d). MSobsd. (ESI⁺) [(M+H)⁺]: 470.

Step 5: Preparation of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

9-[(2-Chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(2.0 g, 4.2 mmol, compound 15d) was dissolved in TFA (10 mL) and stirredat 60° C. for 12 hrs. The reaction mixture was concentrated in vacuo,and basified with NaHCO₃ solution. The resulting precipitate wascollected by filtration and purified to give6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (600mg, compound 15e). MS obsd. (ESI⁺) [(M+H)⁺]: 350.

Step 6: Preparation of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one

To a solution of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (300 mg, 0.86 mmol, compound 15e) in THF (7 mL)was added m-CPBA (221 mg, 1.29 mmol) at 0° C. and the reaction mixturewas stirred at 25° C. for 15 min. The mixture was filtered, and washedwith THF (1 mL) three times. The obtained solid was co-evaporated withtoluene two times to give6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (150mg, compound 15f) as a white solid. It was used in the next step withoutfurther purification. MS obsd. (ESI⁺) [(M+H)⁺]: 366. Step 7: Preparationof6-amino-9-[(2-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

To a solution of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (100mg, 0.27 mmol, compound 15f) in Eaton's reagent (1 mL) was added NaN₃(53 mg, 0.81 mmol) and the mixture was stirred at 60° C. for 0.5 hr. Thereaction mixture was added to ice water and basified with 0.88 Nammonium hydroxide solution, extracted with n-BuOH (10 mL) four timesand concentrated in vacuo. The residue was purified by prep-HPLC to give6-amino-9-[(2-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one(35 mg, Example 15) as a white solid. ¹H NMR (400 MHz DMSO-d₆) δ ppm:10.78 (br. s., 1H), 7.51-7.49 (m, 1H), 7.33-7.28 (m, 2H), 7.14-7.12 (m,1H), 7.04 (br. s., 2H), 5.05 (s, 2H), 3.98 (s, 1H), 3.35-3.24 (m, 2H),1.62-1.55 (m, 2H), 0.86 (t, J=7.3 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]:381.

Example 166-Amino-2-(methylsulfonimidoyl)-9-(3-pyridylmethyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-2-methylsulfanyl-5-nitro-N-(3-pyridylmethyl)pyrimidin-4-amine

Compound 16a was prepared in analogy to Example 15, Step 1 by using4-pyridylmethylamine and4,6-dichloro-2-methylsulfanyl-5-nitro-pyrimidine (J & K scientific,Catalog number: J92-058972-5G) instead of (2-chlorophenyl)methylamineand 4,6-dichloro-2-propyl sulfanyl-5-nitro-pyrimidine.6-Chloro-2-methylsulfanyl-5-nitro-N-(3-pyridylmethyl)pyrimidin-4-amine(compound 16a), which was used in the next step without furtherpurification. MS obsd. (ESI⁺) [(M+H)⁺]: 312.

Step 2: Preparation of6-chloro-2-methylsulfanyl-N4-(3-pyridylmethyl)pyrimidine-4,5-diamine

Compound 16b was prepared in analogy to Example 15, Step 2 by using6-chloro-2-methyl sulfanyl-5-nitro-N-(3-pyridylmethyl)pyrimidin-4-amine(compound 16a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).6-Chloro-2-methylsulfanyl-N4-(3-pyridylmethyl)pyrimidine-4,5-diamine(700 mg, compound 16b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 282.

Step 3: Preparation of6-chloro-2-methylsulfanyl-9-(3-pyridylmethyl)-7H-purin-8-one

Compound 16c was prepared in analogy to Example 15, Step 3 by using6-chloro-2-methylsulfanyl-N4-(3-pyridylmethyl)pyrimidine-4,5-diamine(compound 16b) instead of6-chloro-N-4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b).6-Chloro-2-methylsulfanyl-9-(3-pyridylmethyl)-7H-purin-8-one (600 mg,compound 16c) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:308.

Step 4: Preparation of6-[(4-methoxyphenyl)methylamino]-2-methylsulfanyl-9-(3-pyridylmethyl)-7H-purin-8-one

Compound 16d was prepared in analogy to Example 15, Step 4 by using6-chloro-2-methylsulfanyl-9-(3-pyridylmethyl)-7H-purin-8-one (compound16c) instead of 6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15c). 6-[(4-Methoxyphenyl)methylamino]-2-methyl sulfanyl-9-(3-pyridylmethyl)-7H-purin-8-one (620 mg,compound 16d) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:409.

Step 5: Preparation of6-amino-2-methylsulfanyl-9-(3-pyridylmethyl)-7H-purin-8-one

Compound 16e was prepared in analogy to Example 15, Step 5 by using6-[(4-methoxyphenyl)methylamino]-2-methylsulfanyl-9-(3-pyridylmethyl)-7H-purin-8-one (compound 16d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d). 6-Amino-2-methylsulfanyl-9-(3-pyridylmethyl)-7H-purin-8-one (380 mg, compound 16e) wasobtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 289.

Step 6: Preparation of6-amino-2-methylsulfinyl-9-(3-pyridylmethyl)-7H-purin-8-one

Compound 16f was prepared in analogy to Example 15, Step 6 by6-amino-2-methylsulfanyl-9-(3-pyridylmethyl)-7H-purin-8-one (compound16e) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15e).6-Amino-2-methylsulfinyl-9-(3-pyridylmethyl)-7H-purin-8-one (105 mg,compound 16f) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:305.

Step 7: Preparation of6-amino-2-(methylsulfonimidoyl)-9-(3-pyridylmethyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 6-amino-2-methylsulfinyl-9-(3-pyridylmethyl)-7H-purin-8-one (200mg, compound 16f) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (compound 15f). 6-Amino-2-(methylsulfonimidoyl)-9-(3-pyridylmethyl)-7H-purin-8-one (38.2 mg, Example 16)was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.63 (s,1H), 8.50 (d, J=4.52 Hz, 1H), 7.77 (d, J=8.03 Hz, 1H), 7.38 (dd, J=7.78,5.02 Hz, 1H), 7.00 (br. s., 2H), 5.01 (s, 2H), 4.11 (br. s, 1H), 3.19(s, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 320.

Separation of compound of Example 16 by chiral HPLC afforded Example16-A (faster eluting, 5.0 mg) and Example 16-B (slower eluting, 7.1 mg)as white solid. (Separation condition: methanol 5%-40% (0.05% DEA)/CO₂on ChiralPak OJ-3 column.)

Example 16-A

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.63 (s, 1H), 8.50 (d, J=4.52 Hz, 1H),7.77 (d, J=8.03 Hz, 1H), 7.38 (dd, J=7.78, 5.02 Hz, 1H), 7.00 (br. s.,2H), 5.01 (s, 2H), 4.11 (br. s, 1H), 3.19 (s, 3H). MS obsd. (ESI⁺)[(M+H)⁺]: 320.

Example 16-B

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.63 (s, 1H), 8.50 (d, J=4.52 Hz, 1H),7.77 (d, J=8.03 Hz, 1H), 7.38 (dd, J=7.78, 5.02 Hz, 1H), 7.00 (br. s.,2H), 5.01 (s, 2H), 4.11 (br. s, 1H), 3.19 (s, 3H). MS obsd. (ESI⁺)[(M+H)⁺]: 320.

Example 17 and Example 183-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzonitrile(compound 17) and3-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzamide(compound 18)

Example 18 Step 1: Preparation of3-[[(6-chloro-5-nitro-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzonitrile

Compound 17a was prepared in analogy to Example 15, Step 1 by using3-(aminomethyl)benzonitrile instead of (2-chlorophenyl)methylamine.3-[[(6-Chloro-5-nitro-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzonitrile(2.75 g, compound 17a) was obtained as a yellow solid. MS obsd. (ESI⁺)[(M+H)⁺]: 364.

Step 2: Preparation of3-[[(5-amino-6-chloro-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzonitrile

Compound 17b was prepared in analogy to Example 15, Step 2 by using3-[[(6-chloro-5-nitro-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzonitrile(compound 17a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).3-[[(5-Amino-6-chloro-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzonitrile(1.1 g, compound 17b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 334.

Step 3: Preparation of3-[(6-chloro-2-propylsulfanyl-8-oxo-7H-purin-9-yl)methyl]benzonitrile

Compound 17c was prepared in analogy to Example 15, Step 3 by using3-[[(5-amino-6-chloro-2-methylsulfanyl-pyrimidin-4-yl)amino]methyl]benzonitrile (compound 17b) insteadof6-chloro-N-4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b).3-[(6-Chloro-2-methylsulfanyl-8-oxo-7H-purin-9-yl)methyl]benzonitrile(700 mg, compound 17c) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 360.

Step 4: Preparation of3-[[6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-8-oxo-7H-purin-9-yl]methyl]benzonitrile

Compound 17d was prepared in analogy to Example 15, Step 4 by using3-[(6-chloro-2-methylsulfanyl-8-oxo-7H-purin-9-yl)methyl]benzonitrile(compound 17c) instead of6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15c). 3-[[6-[(4-Methoxyphenyl)methyl amino]-8-oxo-2-propylsulfanyl-7H-purin-9-yl]methyl]benzonitrile (900 mg, compound 17d) wasobtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 461.

Step 5: Preparation of3-[(6-amino-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzonitrile

Compound 17e was prepared in analogy to Example 15, Step 5 by using3-[[6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-8-oxo-7H-purin-9-yl]methyl]benzonitrile(compound 17d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one (compound 15d).3-[(6-Amino-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzonitrile(600 mg, compound 17e) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 341.

Step 6: Preparation of3-[(6-amino-8-oxo-2-propylsulfinyl-7H-purin-9-yl)methyl]benzonitrile

Compound 17f was prepared in analogy to Example 15, Step 6 by using6-amino-2-propylsulfanyl-9-(2-pyridylmethyl)-7H-purin-8-one (compound17e) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15e).3-[(6-Amino-8-oxo-2-propylsulfinyl-7H-purin-9-yl)methyl]benzonitrile(610 mg, compound 17f) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 357.

Step 7: Preparation of3-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzonitrile(compound 17) and3-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzamide(compound 18)

The title compound was prepared in analogy to Example 15, Step 7 byusing 6-amino-2-methyl sulfinyl-9-(2-pyridylmethyl)-7H-purin-8-one (270mg, compound 17f) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (compound 15f).3-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzonitrile(5 mg, Example 17) and3-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzamide(41 mg, Example 18) was obtained as white solid.

Compound 17: ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.62 (br. s, 1H),7.76-7.80 (m, 2H), 7.66 (d, J=8 Hz, 1H), 7.53-7.57 (m, 1H), 6.99 (br. s,2H), 5.02 (s, 2H), 4.05 (s, 1H), 3.28-3.31 (m, 2H), 1.57-1.65 (m, 2H),0.89 (t, J=8.0 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 372.

Compound 18: ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.85 (br. s, 1H), 7.97(s, 1H), 7.84 (s, 1H), 7.77 (d, J=8 Hz, 1H), 7.47 (d, J=8 Hz, 1H),7.37-7.42 (m, 2H), 7.06 (br. s, 2H), 5.00 (s, 2H), 4.01 (s, 1H),3.28-3.30 (m, 2H), 1.55-1.67 (m, 2H), 0.88 (t, J=8.0 Hz, 3H). MS obsd.(ESI⁺) [(M+H)⁺]: 390.

Example 196-Amino-2-(methylsulfonimidoyl)-9-(2-pyridylmethyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-2-methylsulfanyl-5-nitro-N-(2-pyridylmethyl)pyrimidin-4-amine

Compound 19a was prepared in analogy to Example 15, Step 1 by using2-pyridylmethylamine and4,6-dichloro-2-methylsulfanyl-5-nitro-pyrimidine instead of(2-chlorophenyl)methylamine and 2-chlorophenylmethylamine and4,6-dichloro-2-propylsulfanyl-5-nitro-pyrimidine. 6-Chloro-2-methylsulfanyl-5-nitro-N-(2-pyridylmethyl)pyrimidin-4-amine (4.64 g, compound19a) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 312.

Step 2: Preparation of6-chloro-2-methylsulfanyl-N4-(2-pyridylmethyl)pyrimidine-4,5-diamine

Compound 19b was prepared in analogy to Example 15, Step 2 by using6-chloro-2-methyl sulfanyl-5-nitro-N-(2-pyridylmethyl)pyrimidin-4-amine(compound 19a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).6-Chloro-2-methylsulfanyl-N4-(2-pyridylmethyl)pyrimidine-4,5-diamine(2.3 g, compound 19b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 282.

Step 3: Preparation of6-chloro-2-methylsulfanyl-9-(2-pyridylmethyl)-7H-purin-8-one

Compound 19c was prepared in analogy to Example 15, Step 3 by using6-chloro-2-methyl sulfanyl-N4-(2-pyridylmethyl)pyrimidine-4,5-diamine(compound 19b) instead of6-chloro-N-4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b).6-Chloro-2-methylsulfanyl-9-(2-pyridylmethyl)-7H-purin-8-one (2.0 g,compound 19c) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:308.

Step 4: Preparation of6-[(4-methoxyphenyl)methylamino]-2-methylsulfanyl-9-(2-pyridylmethyl)-7H-purin-8-one

Compound 19d was prepared in analogy to Example 15, Step 4 by using6-chloro-2-methylsulfanyl-9-(2-pyridylmethyl)-7H-purin-8-one (compound19c) instead of 6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15c). 6-[(4-Methoxyphenyl)methylamino]-2-methyl sulfanyl-9-(2-pyridylmethyl)-7H-purin-8-one (2.0 g,compound 19d) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:409.

Step 5: Preparation of6-amino-2-methylsulfanyl-9-(2-pyridylmethyl)-7H-purin-8-one

Compound 19e was prepared in analogy to Example 15, Step 5 by using6-[(4-methoxyphenyl)methylamino]-2-methylsulfanyl-9-(2-pyridylmethyl)-7H-purin-8-one(compound 19d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d). 6-Amino-2-methylsulfanyl-9-(2-pyridylmethyl)-7H-purin-8-one (1.14 g, compound 19e) wasobtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 289.

Step 6: Preparation of6-amino-2-methylsulfinyl-9-(2-pyridylmethyl)-7H-purin-8-one

Compound 19f was prepared in analogy to Example 15, Step 6 by using6-amino-2-methyl sulfanyl-9-(2-pyridylmethyl)-7H-purin-8-one (compound19e) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15e).6-Amino-2-methylsulfinyl-9-(2-pyridylmethyl)-7H-purin-8-one (280 mg,compound 19f) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:305.

Step 7: Preparation of6-amino-2-(methylsulfonimidoyl)-9-(2-pyridylmethyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 6-amino-2-methyl sulfinyl-9-(2-pyridylmethyl)-7H-purin-8-one(compound 19f) instead6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 15f). 6-Amino-2-(methylsulfonimidoyl)-9-(2-pyridylmethyl)-7H-purin-8-one (50 mg, Example 19)was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.47 (d,J=4.27 Hz, 1H), 7.77 (td, J=7.65, 1.51 Hz, 1H), 7.24-7.33 (m, 2H), 7.19(br. s., 2H), 5.09 (s, 2H), 4.00 (br. s., 1H), 3.11 (s, 3H). MS obsd.(ESI⁺) [(M+H)⁺]: 320.

Example 206-Amino-2-(methylsulfonimidoyl)-9-(4-pyridylmethyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-2-methylsulfanyl-5-nitro-N-(4-pyridylmethyl)pyrimidin-4-amine

Compound 20a was prepared in analogy to Example 15, Step 1 by using4-pyridylmethylamine and4,6-dichloro-2-methylsulfanyl-5-nitro-pyrimidine instead of(2-chlorophenyl)methylamine and 4,6-dichloro-2-propylsulfanyl-5-nitro-pyrimidine. 6-Chloro-2-methylsulfanyl-5-nitro-N-(4-pyridylmethyl)pyrimidin-4-amine (1.0 g, compound20a) was obtained as a yellow solid. MS obsd. (ESI⁺) [(M+H)⁺]: 312.

Step 2: Preparation of6-chloro-2-methylsulfanyl-N4-(4-pyridylmethyl)pyrimidine-4,5-diamine

Compound 20b was prepared in analogy to Example 15, Step 2 by using6-chloro-2-methyl sulfanyl-5-nitro-N-(4-pyridylmethyl)pyrimidin-4-amine(compound 20a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).6-Chloro-2-methylsulfanyl-N4-(4-pyridylmethyl)pyrimidine-4,5-diamine(900 mg, compound 20b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 282.

Step 3: Preparation of6-chloro-2-methylsulfanyl-9-(4-pyridylmethyl)-7H-purin-8-one

Compound 20c was prepared in analogy to Example 15, Step 3 by using6-chloro-2-methyl sulfanyl-N4-(4-pyridylmethyl)pyrimidine-4,5-diamine(compound 20b) instead of6-chloro-N-4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b).6-Chloro-2-methylsulfanyl-9-(4-pyridylmethyl)-7H-purin-8-one (620 mg,compound 20c) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:308.

Step 4: Preparation of6-[(4-methoxyphenyl)methylamino]-2-methylsulfanyl-9-(4-pyridylmethyl)-7H-purin-8-one

Compound 20d was prepared in analogy to Example 15, Step 4 by using6-Chloro-2-methyl sulfanyl-9-(4-pyridylmethyl)-7H-purin-8-one (compound20c) instead of 6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15c). 6-[(4-Methoxyphenyl)methylamino]-2-methyl sulfanyl-9-(4-pyridylmethyl)-7H-purin-8-one (700 mg,compound 20d) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:409.

Step 5: Preparation of6-amino-2-methylsulfanyl-9-(4-pyridylmethyl)-7H-purin-8-one

Compound 20e was prepared in analogy to Example 15, Step 5 by using6-[(4-methoxyphenyl)methylamino]-2-methylsulfanyl-9-(4-pyridylmethyl)-7H-purin-8-one (compound 20d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d). 6-Amino-2-methylsulfanyl-9-(4-pyridylmethyl)-7H-purin-8-one (450 mg, compound 20e) wasobtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 289.

Step 6: Preparation of6-amino-2-methylsulfinyl-9-(4-pyridylmethyl)-7H-purin-8-one

Compound 20f was prepared in analogy to Example 15, Step 6 by using6-amino-2-methyl sulfanyl-9-(4-pyridylmethyl)-7H-purin-8-one (compound20e) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e). 6-Amino-2-methylsulfinyl-9-(4-pyridylmethyl)-7H-purin-8-one (160 mg, compound 20f) wasobtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 305.

Step 7: Preparation of6-amino-2-(methylsulfonimidoyl)-9-(4-pyridylmethyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 6-amino-2-methylsulfinyl-9-(4-pyridylmethyl)-7H-purin-8-one (200mg, compound 20f) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (compound 15f).6-Amino-2-(methylsulfonimidoyl)-9-(4-pyridylmethyl)-7H-purin-8-one (27mg, Example 20) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm: 8.52 (d, J=5.77 Hz, 2H), 7.29 (d, J=5.52 Hz, 2H), 7.05 (br. s.,2H), 5.01 (s, 2H), 4.06 (s, 1H), 3.16 (s, 3H). MS obsd. (ESI⁺) [(M+H)⁺]:320.

Example 21 6-Amino-9-isobutyl-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-N-isobutyl-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 21a was prepared in analogy to Example 15, Step 1 by using2-methylpropan-1-amine instead of (2-chlorophenyl)methylamine.6-Chloro-N-isobutyl-5-nitro-2-propylsulfanyl-pyrimidin-4-amine (compound21a) was obtained as a light yellow solid. MS obsd. (ESI⁺) [(M+H)⁺]:305.

Step 2: Preparation of6-chloro-N4-isobutyl-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 21b was prepared in analogy to Example 15, Step 2 by using6-chloro-N-isobutyl-5-nitro-2-propylsulfanyl-pyrimidin-4-amine (compound21a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).6-Chloro-N4-isobutyl-2-propylsulfanyl-pyrimidine-4,5-diamine (4.5 g,compound 21b) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:275.

Step 3: Preparation of6-chloro-9-isobutyl-2-propylsulfanyl-7H-purin-8-one

Compound 21c was prepared in analogy to Example 15, Step 3 by using6-chloro-N4-isobutyl-2-propylsulfanyl-pyrimidine-4,5-diamine (compound21b) instead of6-chloro-N-4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b). 6-Chloro-9-isobutyl-2-propylsulfanyl-7H-purin-8-one (850mg, compound 21c) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 301.

Step 4: Preparation of9-isobutyl-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one

Compound 21d was prepared in analogy to Example 15, Step 4 by using6-chloro-9-isobutyl-2-propylsulfanyl-7H-purin-8-one (compound 21c)instead of6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15c).9-Isobutyl-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(570 mg, compound 21d) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 402.

Step 5: Preparation of6-amino-9-isobutyl-2-propylsulfanyl-7H-purin-8-one

Compound 21e was prepared in analogy to Example 15, Step 5 by using9-isobutyl-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one (compound 21d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d). 6-Amino-9-isobutyl-2-propyl sulfanyl-7H-purin-8-one (300mg, compound 21e) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 282.

Step 6: Preparation of6-amino-9-isobutyl-2-propylsulfinyl-7H-purin-8-one

Compound 21f was prepared in analogy to Example 15, Step 6 by using6-amino-9-isobutyl-2-propyl sulfanyl-7H-purin-8-one (compound 21e)instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e). 6-Amino-9-isobutyl-2-propylsulfinyl-7H-purin-8-one (125mg, compound 21f) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 298.

Step 7: Preparation of6-amino-2-(methylsulfonimidoyl)-9-(4-pyridylmethyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 6-amino-9-isobutyl-2-propyl sulfinyl-7H-purin-8-one (compound 21f)instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (compound 15f).6-Amino-9-isobutyl-2-(propylsulfonimidoyl)-7H-purin-8-one (65.8 mg,Example 21) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δppm: 10.46 (s, 1H), 6.92 (br. s., 2H), 4.00 (s, 1H), 3.59 (d, J=1.6 Hz,2H), 3.32-3.38 (m, 2H), 2.15 (m, 1H), 1.65-1.73 (m, 2H), 0.97 (t, J=73Hz, 3H), 0.86 (m, 6H). MS obsd. (ESI⁺) [(M+H)⁺]: 313.

Example 226-Amino-9-[(3-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-N-[(3-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 22a was prepared in analogy to Example 15, Step 1 by using(3-chlorophenyl)methylamine instead of (2-chlorophenyl)methyl amine.6-Chloro-N-[(3-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(13.9 g, compound 22a) was obtained as a yellow solid. MS obsd. (ESI⁺)[(M+H)⁺]: 373.

Step 2: Preparation of6-chloro-N4-[(3-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 22b was prepared in analogy to Example 15, Step 2 by using6-chloro-N-[(3-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 22a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).6-Chloro-N4-[(3-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(13.0 g, compound 22b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 343.

Step 3: Preparation of6-chloro-9-[(3-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 22c was prepared in analogy to Example 15, Step 3 by using6-chloro-N-4-[(3-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 22b) instead of6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b). 6-Chloro-9-[(3-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (13.0 g, compound 22c) was obtained as a whitesolid. MS obsd. (ESI⁺) [(M+H)⁺]: 369.

Step 4: Preparation of9-[(3-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one

Compound 22d was prepared in analogy to Example 15, Step 4 by using6-chloro-9-[(3-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 22c) instead of6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15c).9-[(3-Chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one (6.0 g, compound 22d) was obtained as a whitesolid. MS obsd. (ESI⁺) [(M+H)⁺]: 470.

Step 5: Preparation of6-amino-9-[(3-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 22e was prepared in analogy to Example 15, Step 5 by using9-[(3-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one (compound 22d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d).6-Amino-9-[(3-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (300mg, compound 22e) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 350.

Step 6: Preparation of6-amino-9-[(3-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one

Compound 22f was prepared in analogy to Example 15, Step 6 by using6-amino-9-[(3-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 22e) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15e).6-Amino-9-[(3-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (150mg, compound 22f) was obtained as a yellow solid. MS obsd. (ESI⁺)[(M+H)⁺]: 366.

Step 7: Preparation of6-amino-9-[(3-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 6-amino-9-[(3-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(100 mg, compound 22f) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 15f). 6-Amino-9-[(3-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one (43 mg, Example 22) was obtained as awhite solid. ¹H NMR (400 MHz DMSO-d₆) δ ppm: 7.41-7.36 (m, 3H),7.030-7.28 (m, 1H), 7.01 (br. s., 2H), 4.96 (s, 2H), 4.03 (s, 1H),3.34-3.27 (m, 2H), 1.67-1.59 (m, 2H), 0.91 (t, J=8.0 Hz, 3H). MS obsd.(ESI⁺) [(M+H)⁺]: 381.

Example 236-Amino-2-(propylsulfonimidoyl)-9-[[4-(trifluoromethyl)phenyl]methyl]-7H-purin-8-one

Step 1: Preparation of6-chloro-N-[(4-trifluoromethylphenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 23a was prepared in analogy to Example 15, Step 1 by using(4-trifluoromethylphenyl)methylamine instead of(2-chlorophenyl)methylamine.6-Chloro-N-[(4-trifluoromethylphenylmethyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine (7.0 g, compound 23a) was obtained as a whitesolid. MS obsd. (ESI⁺) [(M+H)⁺]: 407.

Step 2: Preparation of6-chloro-2-propylsulfanyl-N4-[[4-(trifluoromethyl)phenyl]methyl]pyrimidine-4,5-diamine

Compound 23b was prepared in analogy to Example 15, Step 2 by using6-chloro-N-[(4-trifluoromethylphenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 23a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).6-Chloro-N4-[(4-trifluoromethylphenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(3.1 g, compound 23b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 377.

Step 3: Preparation of6-chloro-9-[(4-trifluoromethylphenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 23c was prepared in analogy to Example 15, Step 3 by using6-chloro-N-4-[(4-trifluoromethylphenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 23b) instead of 6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine (compound 15b).6-Chloro-9-[(4-trifluoromethylphenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(1.8 g, compound 23c) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 403.

Step 4: Preparation of6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-9-[[4-(trifluoromethyl)phenyl]methyl]-7H-purin-8-one

Compound 23d was prepared in analogy to Example 15, Step 4 by using6-chloro-9-[(4-trifluoromethylphenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 23c) instead of6-chloro-9-[(2-chlorophenyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(compound 15c).9-[(4-Trifluoromethylphenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one (1.2 g, compound 23d) was obtained as a whitesolid. MS obsd. (ESI⁺) [(M+H)⁺]: 504.

Step 5: Preparation of6-amino-9-[(4-trifluoromethylphenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 23e was prepared in analogy to Example 15, Step 5 by using9-[(4-trifluoromethylphenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 23d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d).6-Amino-9-[(4-trifluoromethylphenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(900 mg, compound 23e) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 384.

Step 6: Preparation of6-amino-2-propylsulfinyl-9-[[4-(trifluoromethyl)phenyl]methyl]-7H-purin-8-one

Compound 23f was prepared in analogy to Example 15, Step 6 by using6-amino-9-[(4-trifluoromethylphenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 23e) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e).6-Amino-2-propylsulfinyl-9-[[4-(trifluoromethyl)phenyl]methyl]-7H-purin-8-one(200 mg, compound 23f) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 400.

Step 7: Preparation of6-amino-2-(propylsulfonimidoyl)-9-[[4-(trifluoromethyl)phenyl]methyl]-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 6-amino-9-[(4-trifluoromethylphenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (200 mg, compound 23f) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 15f). 6-Amino-2-(propylsulfonimidoyl)-9-[[4-(trifluoromethyl)phenyl]methyl]-7H-purin-8-one (57mg, Example 23) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm: 7.70 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.01 (br. s.,2H), 5.07 (s, 2H), 4.06 (s, 1H), 3.41-3.27 (m, 2H), 1.6-1.57 (m, 2H),0.86 (t, J=8.0 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 415.

Example 246-Amino-9-[(4-fluorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-N-[(4-fluorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 24a was prepared in analogy to Example 15, Step 1 by using(4-fluorophenyl)methylamine instead of (2-chlorophenyl)methylamine.6-Chloro-N-[(4-fluorophenylmethyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(6.4 g, compound 24a) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 357.

Step 2: Preparation of6-chloro-N4-[(4-fluorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 24b was prepared in analogy to Example 15, Step 2 by using6-chloro-N-[(4-fluorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 24a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).6-Chloro-N4-[(4-fluorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(6.0 g, compound 24b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 327.

Step 3: Preparation of6-chloro-9-[(4-fluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 24c was prepared in analogy to Example 15, Step 3 by using6-chloro-N-4-[(4-fluorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 24b) instead of6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b). 6-Chloro-9-[(4-fluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (5.0 g, compound 24c) was obtained as a whitesolid. MS obsd. (ESI⁺) [(M+H)⁺]: 353.

Step 4: Preparation of9-[(4-fluorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one

Compound 24d was prepared in analogy to Example 15, Step 4 by using6-chloro-9-[(4-fluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 24c) instead of 6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15c).9-[(4-Fluorophenyl)methyl]-6-[(4-methoxyphenyl)methyl amino]-2-propylsulfanyl-7H-purin-8-one (5.5 g, compound 24d) was obtained as a whitesolid. MS obsd. (ESI⁺) [(M+H)⁺]: 454.

Step 5: Preparation of6-amino-9-[(4-fluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 24e was prepared in analogy to Example 15, Step 5 by using9-[(4-fluorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one (compound 24d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d).6-Amino-9-[(4-fluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (600mg, compound 24e) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 334.

Step 6: Preparation of6-amino-2-propylsulfinyl-9-[4-fluorophenylmethyl]-7H-purin-8-one

Compound 24f was prepared in analogy to Example 15, Step 6 by using6-amino-9-[(4-fluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 24e) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e).6-Amino-2-propylsulfinyl-9-[[4-fluorophenyl]methyl]-7H-purin-8-one (530mg, compound 24f) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 350.

Step 7: Preparation of6-amino-2-(propylsulfonimidoyl)-9-[[4-(trifluoromethyl)phenyl]methyl]-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 5 byusing 6-amino-9-[(4-fluorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(250 mg, compound 24f) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 15f). 6-Amino-2-(propylsulfonimidoyl)-9-[[4-fluorophenyl]methyl]-7H-purin-8-one (41.6 mg,Example 24) was obtained as a gray solid. ¹H NMR (400 MHz, DMSO-d₆) δppm: 10.62 (br. s., 1H), 7.40-7.38 (m, 2H), 7.18-7.16 (m, 2H), 7.00 (br.s., 2H), 4.95 (s, 2H), 4.05 (s, 1H), 3.33-3.30 (m, 2H), 1.74-1.55 (m,2H), 0.92 (t, J=8.0 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 365.

Example 256-Amino-9-[(4-bromophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-N-[(4-bromophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 25a was prepared in analogy to Example 15, Step 1 by using(4-bromophenyl)methyl amine instead of (2-chlorophenyl)methylamine.6-Chloro-N-[(4-bromophenylmethyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(7.0 g, compound 25a) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 417.

Step 2: Preparation of6-chloro-N4-[(4-bromophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 25b was prepared in analogy to Example 15, Step 2 by using6-chloro-N-[(4-bromophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 25a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).6-Chloro-N4-[(4-bromophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(3.2 g, compound 25b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 387.

Step 3: Preparation of6-chloro-9-[(4-bromophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 25c was prepared in analogy to Example 15, Step 3 by using6-chloro-N-4-[(4-bromophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 25b) instead of6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b).6-Chloro-9-[(4-bromophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (2.5g, compound 25c) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 413.

Step 4: Preparation of9-[(4-bromophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one

Compound 25d was prepared in analogy to Example 15, Step 4 by using6-chloro-9-[(4-bromophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 25c) instead of 6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15c).9-[(4-Bromophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one (3.1 g, compound 25d) was obtained as a whitesolid. MS obsd. (ESI⁺) [(M+H)⁺]: 514.

Step 5: Preparation of6-amino-9-[(4-bromophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 25e was prepared in analogy to Example 15, Step 5 by using9-[(4-bromophenyl)methyl]-6-[(4-methoxyphenyl)methyl amino]-2-propylsulfanyl-7H-purin-8-one (compound 25d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d).6-Amino-9-[(4-bromophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (1.1g, compound 25e) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 394.

Step 6: Preparation of6-amino-2-propylsulfinyl-9-[4-bromophenylmethyl]-7H-purin-8-one

Compound 25f was prepared in analogy to Example 15, Step 5 by using6-amino-9-[(4-bromophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 25e) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e).6-Amino-2-propylsulfinyl-9-[[4-bromophenyl]methyl]-7H-purin-8-one (250mg, compound 25f) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 410.

Step 7: Preparation of6-amino-2-(propylsulfonimidoyl)-9-[[4-bromophenyl]methyl]-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 5 byusing 6-amino-9-[(4-bromophenyl)methyl]-2-propyl sulfinyl-7H-purin-8-one(260 mg, compound 25f) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 15f). 6-Amino-2-(propylsulfonimidoyl)-9-[[4-bromophenyl]methyl]-7H-purin-8-one (70 mg, Example25) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm:10.62 (br. s., 1H), 7.53 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 6.99(br. s., 2H), 4.94 (s, 2H), 4.04 (s, 1H), 3.35-3.25 (m, 2H), 1.67-1.56(m, 2H), 0.90 (t, J=8.0 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 425.

Example 266-Amino-9-[(3,4-dichlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-N-[(3,4-dichlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 26a was prepared in analogy to Example 15, Step 1 by using(3,4-dichlorophenyl)methylamine instead of (2-chlorophenyl)methyl amine.6-Chloro-N-[(4-bromophenylmethyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(3.6 g, compound 26a) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 425.

Step 2: Preparation of6-chloro-N4-[(3,4-dichlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 26b was prepared in analogy to Example 15, Step 2 by using6-chloro-N-[(3,4-dichlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 26a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).6-Chloro-N4-[(3,4-dichlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(3.1 g, compound 26b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 377.

Step 3: Preparation of6-chloro-9-[(3,4-dichlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 26c was prepared in analogy to Example 15, Step 3 by using6-chloro-N-4-[(3,4-dichlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 26b) instead of6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b).6-Chloro-9-[(3,4-dichlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(1.8 g, compound 26c) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 403.

Step 4: Preparation of9-[(3,4-dichlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one

Compound 26d was prepared in analogy to Example 15, Step 4 by using6-chloro-9-[(3,4-di chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 26c) instead of6-chloro-9-[(2-chlorophenyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(compound 15c).9-[(3,4-Dichlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(1.6 g, compound 26d) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 504.

Step 5: Preparation of6-amino-9-[(3,4-dichlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 26e was prepared in analogy to Example 15, Step 5 by using9-[(3,4-dichlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 26d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d).6-Amino-9-[(3,4-dichlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(900 mg, compound 26e) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 384.

Step 6: Preparation of6-amino-2-propylsulfinyl-9-[3,4-dichlorophenyl]-7H-purin-8-one

Compound 26f was prepared in analogy to Example 15, Step 6 by using6-amino-9-[(3,4-di chlorophenyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(compound 26e) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e).6-Amino-2-propylsulfinyl-9-[[3,4-dichlorophenyl]methyl]-7H-purin-8-one(210 mg, compound 26f) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 401.

Step 7: Preparation of6-amino-2-(propylsulfonimidoyl)-9-(3,4-dichlorophenylmethyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 6-amino-9-[(3,4-dichlorophenylmethyl]-2-propylsulfinyl-7H-purin-8-one (compound 26f) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propyl sulfinyl-7H-purin-8-one(compound 15f).6-Amino-2-(propylsulfonimidoyl)-9-(3,4-dichlorophenylmethyl)-7H-purin-8-one(47 mg, Example 26) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 10.67 (br. s., 1H), 7.63-7.59 (m, 2H), 7.32-7.29 (m,1H), 7.01 (br. s., 2H), 4.98 (s, 2H), 4.05 (s, 1H), 3.35-3.30 (m, 2H),1.67-1.56 (m, 2H), 0.90 (t, J=8.0 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]:415.

Example 276-Amino-9-(3,4-difluorophenylmethyl)-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-N-[(3,4-difluorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 27a was prepared in analogy to Example 15, Step 1 by using(3,4-difluorophenyl)methylamine instead of (2-chlorophenyl)methylamine.6-Chloro-N-[(3,4-difluorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(3.1 g, compound 27a) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 375.

Step 2: Preparation of6-chloro-N4-[(3,4-difluorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 27b was prepared in analogy to Example 15, Step 2 by using6-chloro-N-[(3,4-difluorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 27a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).6-Chloro-N-4-[(3,4-difluorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(2.2 g, compound 27b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 345.

Step 3: Preparation of6-chloro-9-[(3,4-difluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 27c was prepared in analogy to Example 15, Step 3 by using6-chloro-N4-[(3,4-difluorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 27b) instead of 6-chloro-N-4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine (compound 15b).6-Chloro-9-[(3,4-difluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(1.6 g, compound 27c) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 371.

Step 4: Preparation of9-[(3,4-difluorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one

Compound 27d was prepared in analogy to Example 15, Step 4 by using6-chloro-9-[(3,4-difluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 27c) instead of6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15c).9-[(3,4-Difluorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(1.5 g, compound 27d) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 472.

Step 5: Preparation of6-amino-9-[(3,4-difluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 27e was prepared in analogy to Example 15, Step 5 by using9-[(3,4-difluorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 27d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d).6-Amino-9-[(3,4-difluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(600 mg, compound 27e) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 352.

Step 6: Preparation of6-amino-2-propylsulfinyl-9-[3,4-difluorophenyl)methyl]-7H-purin-8-one

Compound 27f was prepared in analogy to Example 15, Step 6 by using6-amino-9-[(3,4-difluorophenyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(compound 27e) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15e).6-Amino-2-propylsulfinyl-9-[[3,4-difluorophenyl)methyl]-7H-purin-8-one(150 mg, compound 27f) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 368.

Step 7: Preparation of6-amino-9-[(3,4-difluorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing6-amino-9-[(3,4-difluorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 27f) instead 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (compound 15f).6-Amino-2-(propylsulfonimidoyl)-9-[[3,4-difluorophenyl)methyl]-7H-purin-8-one(60 mg, Example 27) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 10.65 (br. s., 1H), 7.46-7.36 (m, 2H), 7.19-7.18 (m,1H), 6.98 (br. s., 2H), 4.96 (s, 2H), 4.04 (s, 1H), 3.35-3.26 (m, 2H),1.67-1.57 (m, 2H), 0.91 (t, J=8.0 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]:383.

Example 286-Amino-9-[(4-chloro-3-methyl-phenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of 4-chloro-3-methylbenzamide

To an ice cooled solution of 4-chloro-3-methylbenzoic acid (20.0 g,117.2 mmol), HOBt (15.8 g, 117.2 mmol) and NH₄Cl (18.8 g, 351.7 mmol) inanhydrous DMF (200 mL) was added DIPEA (45.5 g, 351.7 mmol) followed byEDC-HCl (27.4 g, 152.4 mmol), then the mixture was warmed to 25° C. andstirred for 20 hrs. The reaction mixture was diluted with water (1.2 L)and extracted with EtOAC (200 mL) three times. The combined organiclayer was washed with 1N HCl aq., sat.

Na₂CO₃ aq., brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was triturated with MTBE to give4-chloro-3-methylbenzamide (15 g, compound 28a) as a light yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.00 (s, 1H), 7.86 (s, 1H), 7.71 (dd,J=8.3 Hz, 1.5 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.42 (s, 1H), 2.37 (s,3H). MS obsd. (ESI⁺) [(M+H)⁺]: 170.

Step 2: Preparation of (4-chloro-3-methylphenyl)methylamine

To a suspension of LiAlH₄ (11.2 g, 294.8 mmol) in anhydrous THF (100 mL)was added 3-chloro-4-methyl-benzamide (10 g, 58.96 mmol) in THF (100 mL)drop-wise. After the addition, the mixture was stirred at 28° C. for 2hrs and then heated to 60° C. for 12 hrs. After the reaction mixture wascooled to 0° C., then 11.2 mL of water, 11.2 mL of 15% NaOH aq. and 33.6mL of water was added sequentially. Anhydrous sodium sulfate (20 g) wasadded, and the resulting suspension was stirred for 30 min, andfiltered. The filtrate was concentrated in vacuo to obtain(4-chloro-3-methyl-phenyl)methylamine as a colorless oil (8 g, compound28b). MS obsd. (ESI⁺) [(M+H)⁺]: 156.

Step 3: Preparation of6-chloro-N-[(4-chloro-3-methyl-phenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 28c was prepared in analogy to Example 15, Step 1 by using(4-chloro-3-methyl-phenyl)methylamine instead of(2-chlorophenyl)methylamine.6-Chloro-N-[(4-chloro-3-methylphenylmethyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(8.0 g, compound 28c) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 387.

Step 4: Preparation of6-chloro-N4-[(4-chloro-3-methyl-phenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 28d was prepared in analogy to Example 15, Step 2 by using6-chloro-N-[(4-chloro-3-methylphenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 28c) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine (compound 15a).6-Chloro-N-4-[(4-chloro-3-methylphenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine (4.4 g, compound 28d) was obtained as awhite solid. MS obsd. (ESI⁺) [(M+H)⁺]: 357.

Step 5: Preparation of6-chloro-9-[(4-chloro-3-methyl-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 28e was prepared in analogy to Example 15, Step 3 by using6-chloro-N4-[(4-chloro-3-methylphenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 28d) instead of6-chloro-N-4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b).6-Chloro-9-[(4-chloro-3-methyl-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(4.6 g, compound 28e) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 383.

Step 6: Preparation of9-[(4-chloro-3-methyl-phenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one

Compound 28f was prepared in analogy to Example 15, Step 4 by using6-chloro-9-[(4-chloro-3-methylphenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 28e) instead of 6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15c).9-[(3-Chloro-4-methyl-phenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one (9 g, compound 28f) was obtained as a whitesolid. MS obsd. (ESI⁺) [(M+H)⁺]: 484.

Step 7: Preparation of6-amino-9-[(4-chloro-3-methyl-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 28g was prepared in analogy to Example 15, Step 5 by using9-[(4-chloro-3-methyl-phenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one (compound 28f) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d).6-Amino-9-[(4-chloro-3-methyl-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(4.5 g, compound 28g) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 364.

Step 8: Preparation of6-amino-2-propylsulfinyl-9-[4-chloro-3-methyl-phenylmethyl]-7H-purin-8-one

Compound 28h was prepared in analogy to Example 15, Step 6 by using6-amino-9-[(3-chloro-4-methyl-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 28g) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e). 6-Amino-2-propylsulfinyl-9-[[4-chloro-3-methyl-phenyl]methyl]-7H-purin-8-one (340 mg,compound 28h) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:380.

Step 9: Preparation of6-amino-9-[(4-chloro-3-methyl-phenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 6-amino-9-[(4-chloro-3-methyl-phenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (compound 28h) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propyl sulfinyl-7H-purin-8-one.6-Amino-2-(propylsulfonimidoyl)-9-[[4-chloro-3-methyl-phenyl]methyl]-7H-purin-8-one (80mg, Example 28) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm: 7.37-7.33 (m, 2H), 7.18-7.16 (m, 2H), 6.97 (br. s., 2H), 4.92 (s,2H), 4.04 (s, 1H), 3.33-3.31 (m, 2H), 2.29 (s, 3H), 1.65-1.61 (m, 2H),0.90 (t, J=7.6 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 395.

Example 296-Amino-2-(propylsulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-N-[(p-tolylmethyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 29a was prepared in analogy to Example 15, Step 1 by usingp-tolylmethylamine instead of (2-chlorophenyl)methylamine.6-Chloro-N-[(p-tolylmethyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(3.9 g, compound 29a) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 353.

Step 2: Preparation of6-chloro-N4-[(p-tolylmethyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 29b was prepared in analogy to Example 15, Step 2 by using6-chloro-N-[(p-tolylmethyl-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 29a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).6-Chloro-N4-(p-tolylmethyl)-2-propylsulfanyl-pyrimidine-4,5-diamine (2.2g, compound 29b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 323.

Step 3: Preparation of6-chloro-9-[(p-tolylmethyl]-2-propylsulfanyl-7H-purin-8-one

Compound 29c was prepared in analogy to Example 15, Step 3 by using6-chloro-N4-[(p-tolylmethyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 29b) instead of6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b).6-Chloro-9-[(p-tolylmethyl]-2-propylsulfanyl-7H-purin-8-one (2.2 g,compound 29c) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:349.

Step 4: Preparation of9-[(p-tolylmethyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one

Compound 29d was prepared in analogy to Example 15, Step 4, by using6-chloro-9-[(p-tolylmethyl]-2-propyl sulfanyl-7H-purin-8-one (compound29c) instead of 6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15c).9-[(p-Tolylmethyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(2.0 g, compound 29d) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 450.

Step 5: Preparation of6-amino-2-propylsulfanyl-9-(p-tolylmethyl)-7H-purin-8-one

Compound 29e was prepared in analogy to Example 15, Step 5 by using9-[(p-tolylmethyl]-6-[(4-methoxyphenyl)methyl amino]-2-propylsulfanyl-7H-purin-8-one (compound 29d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one (compound 15d).6-Amino-9-[(p-tolylmethyl]-2-propyl sulfanyl-7H-purin-8-one (1.0 g,compound 29e) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:330.

Step 6: Preparation of6-amino-2-propylsulfinyl-9-[p-tolylmethyl]-7H-purin-8-one

Compound 29f was prepared in analogy to Example 15, Step 6 by using6-amino-9-[(p-tolylmethyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 29e) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15e).6-Amino-2-propylsulfinyl-9-[p-tolylmethyl]-7H-purin-8-one (220 mg,compound 29f) was obtained as a white solid MS obsd. (ESI⁺) [(M+H)⁺]:345.

Step 7: Preparation of6-amino-2-(propylsulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 6-amino-9-[(p-tolylmethyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 29f) instead 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one.6-Amino-2-(propylsulfonimidoyl)-9-[[p-tolylmethyl]-7H-purin-8-one (127mg, Example 29) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm: 10.67 (br. s., 1H), 7.23 (d, J=8.0 Hz, 2H), 7.13 (d, J=8.0 Hz,2H), 6.98 (br. s., 2H), 4.91 (s, 2H), 4.05 (s, 1H), 3.34-3.27 (m, 2H),2.26 (s, 3H), 1.67-1.62 (m, 2H), 0.92 (t, J=8.0 Hz, 3H). MS obsd. (ESI⁺)[(M+H)⁺]: 361.

Separation of compound of Example 29 by chiral HPLC afforded Example29-A (faster eluting, 50 mg) and Example 29-B (slower eluting, 49 mg) aswhite solid. (Separation condition: 30% isopropanol (0.05% DEA)/CO₂ onChiralPak AD-3 column.)

Example 29-A

¹H NMR: (400 MHz, DMSO-d₆) δ ppm: 10.51 (s, 1H), 7.22 (d, J=8.0 Hz, 2H),7.12 (d, J=8.0 Hz, 2H), 7.00 (s, 2H), 4.91 (s, 2H), 4.03 (s, 1H),3.35-3.31 (m, 2H), 2.26 (s, 3H), 1.70-1.58 (m, 2H), 0.93 (t, J=7.40 Hz,3H). MS obsd. (ESI⁺) [(M+H)⁺]: 361.

Example 29-B

¹H NMR: (400 MHz, DMSO-d₆) δ ppm: 10.54 (s, 1H), 7.23 (d, J=8.0 Hz, 2H),7.13 (d, J=8.0 Hz, 2H), 6.97 (s, 2H), 4.91 (s, 2H), 4.04 (s, 1H),3.34-3.30 (m, 2H), 2.26 (s, 3H), 1.72-1.57 (m, 2H), 0.93 (t, J=7.40 Hz,3H). MS obsd. (ESI⁺) [(M+H)⁺]: 361.

Example 306-Amino-9-[(4-chloro-3-fluorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-N-[(4-chloro-3-fluoro-phenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 30a was prepared in analogy to Example 15, Step 1 by using4-chloro-3-fluorophenyl)methylamine instead of(2-chlorophenyl)methylamine.6-Chloro-N-[(4-chloro-3-fluoro-phenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(6.2 g, compound 30a) was obtained. MS obsd. (ESI⁺) [(M+H)⁺]: 391.

Step 2: Preparation of6-chloro-N4-[(4-chloro-3-fluoro-phenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 30b was prepared in analogy to Example 15, Step 2 by using6-chloro-N-[(4-chloro-3-fluoro-phenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 30a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine (compound 15a).6-Chloro-N4-[4-chloro-3-fluoro-phenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(4.7 g, compound 30b) was obtained as a brown solid. MS obsd. (ESI⁺)[(M+H)⁺]: 361.

Step 3: Preparation of6-chloro-9-[(4-chloro-3-fluoro-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 30c was prepared in analogy to Example 15, Step 3 by using6-chloro-N-4-[(4-chloro-3-fluoro-phenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 30b) instead of6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b).6-Chloro-9-[(4-chloro-3-fluoro-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(3.8 g, compound 30c) was obtained as a gray solid. MS obsd. (ESI⁺)[(M+H)⁺]: 387.

Step 4: Preparation of9-[(4-chloro-3-fluorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one

Compound 30d was prepared in analogy to Example 15, Step 4 by using6-chloro-9-[(4-chloro-3-fluoro-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 30c) instead of6-chloro-9-[(2-chlorophenyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(compound 15c).9-[(4-Chloro-3-fluoro-phenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(2.3 g, compound 30d) was obtained as a light yellow solid. MS obsd.(ESI⁺) [(M+H)⁺]: 488.

Step 5: Preparation of6-amino-9-[(4-chloro-3-fluoro-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 30e was prepared in analogy to Example 15, Step 5 by using9-[(4-chloro-3-fluoro-phenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one (compound 30d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d).6-Amino-9-[(4-chloro-3-fluoro-phenyl)methyl)methyl]-2-propylsulfanyl-7H-purin-8-one(1.4 g, compound 30e) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 368.

Step 6: Preparation of6-amino-2-propylsulfinyl-9-[4-chloro-3-fluoro-phenyl)methyl]-7H-purin-8-one

Compound 30f was prepared in analogy to Example 15, Step 6 by using6-amino-9-[(4-chloro-3-fluoro-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 30e) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e). 6-Amino-2-propylsulfinyl-9-[[4-chloro-3-fluoro-phenyl)methyl]-7H-purin-8-one (300 mg,compound 30f) was obtained as a white solid MS obsd. (ESI⁺) [(M+H)⁺]:384.

Step 7: Preparation of6-amino-2-(propylsulfonimidoyl)-9-[[4-chloro-3-fluoro-phenyl)methyl]methyl]-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 6-amino-9-[(4-chloro-3-fluoro-phenyl)methyl 2-propylsulfinyl-7H-purin-8-one (compound 30f) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(Example 30). 6-Amino-2-(propylsulfonimidoyl)-9-[[4-chloro-3-fluoro-phenyl)methyl]-7H-purin-8-one (63mg, Example 30) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm: 10.67 (br. s., 1H), 7.45-7.34 (m, 1H)), 7.31-7.22 (m, 1H),7.09-7.03 (m, 1H), 7.00 (br. s., 2H), 4.99 (s, 2H), 3.98 (s, 1H),3.31-3.26 (m, 2H), 1.72-1.50 (m, 2H), 0.91 (t, J=8.0 Hz, 3H). MS obsd.(ESI⁺) [(M+H)⁺]: 399.

Example 316-Amino-9-[(2,4-difluorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-N-[(2,4-difluorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 31a was prepared in analogy to Example 15, Step 1 by using(2,4-difluorophenyl)methylamine instead of (2-chlorophenyl)methylamine.6-Chloro-N-[(2,4-difluorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(5.0 g, compound 31a) was obtained as a yellow solid. MS obsd. (ESI⁺)[(M+H)⁺]: 375.

Step 2: Preparation of6-chloro-N4-[(2,4-difluorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 31b was prepared in analogy to Example 15, Step 2 by using6-chloro-N-[(2,4-difluorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 31a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a). 6-Chloro-N4-[(2,4-difluorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine (4.0 g, compound 31b) was obtained as awhite solid. MS obsd. (ESI⁺) [(M+H)⁺]: 345.

Step 3: Preparation of6-chloro-9-[(2,4-difluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 31c was prepared in analogy to Example 15, Step 3 by using6-chloro-N-4-[(2,4-difluorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 31b) instead of6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b).6-Chloro-9-[(2,4-difluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(4.0 g, compound 31c) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 371.

Step 4: Preparation of9-[(2,4-difluorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one

Compound 31d was prepared in analogy to Example 15, Step 4 by using6-chloro-9-[(2,4-difluorophenyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(compound 31c) instead of6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15c).9-[(2,4-Difluorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(2.9 g, compound 31d) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 472.

Step 5: Preparation of6-amino-9-[(2,4-difluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 31e was prepared in analogy to Example 15, Step 5 by using9-[(2,4-difluorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 31d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d).6-Amino-9-[(2,4-difluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(1.4 g, compound 31e) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 352.

Step 6: Preparation of6-amino-2-propylsulfinyl-9-[(2,4-difluorophenyl)methyl]-7H-purin-8-one

Compound 31f was prepared in analogy to Example 15, Step 6 by using6-amino-9-[(2,4-difluorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 31e) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15e).6-Amino-2-propylsulfinyl-9-[[(2,4-difluorophenyl)methyl]-7H-purin-8-one(290 mg, compound 31f) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 368.

Step 7: Preparation of6-amino-2-(propylsulfonimidoyl)-9-[[(2,4-difluorophenyl)methyl]-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing6-amino-9-[(2,4-difluorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 31f) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (compound 15f). 6-Amino-2-(propylsulfonimidoyl)-9-[[(2,4-difluorophenyl)methyl]-7H-purin-8-one (33 mg,compound 31) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δppm: 10.68 (br. s., 1H), 7.56 (t, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H),7.24-7.14 (m, 1H), 7.01 (br. s., 2H), 4.98 (s, 2H), 4.05 (s, 1H),3.32-3.24 (m, 2H), 1.71-1.52 (m, 2H), 0.90 (t, J=8.0 Hz, 3H). MS obsd.(ESI⁺) [(M+H)⁺]: 383.

Example 32 & Example 334-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzonitrile(compound 32) and4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzamide(compound 33)

Step 1: Preparation of4-[[(6-chloro-5-nitro-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzonitrile

Compound 32a was prepared in analogy to Example 15, Step 1 by using4-(aminomethyl)benzonitrile instead of (2-chlorophenyl)methylamine.4-[[(6-chloro-5-nitro-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzonitrile(5.5 g, compound 32a) was obtained as a yellow solid. MS obsd. (ESI⁺)[(M+H)⁺]: 364.

Step 2: Preparation of4-[[(5-amino-6-chloro-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzonitrile

Compound 32b was prepared in analogy to Example 15, Step 2 by using4-[[(6-chloro-5-nitro-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzonitrile(compound 32a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).4-[[(5-Amino-6-chloro-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzonitrile(2.7 g, compound 32b) was obtained as a brown oil. MS obsd. (ESI⁺)[(M+H)⁺]: 334.

Step 3: Preparation of4-[(6-chloro-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzonitrile

Compound 32c was prepared in analogy to Example 15, Step 3 by using4-[[(5-amino-6-chloro-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzonitrile(2.7 g, compound 32b) instead of6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b). 4-[(6-Chloro-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzonitrile (2.5 g, compound 32c) wasobtained as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.14(br. s., 1H), 7.82 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 5.06 (s,2H), 3.01 (t, J=8.0 Hz, 2H), 1.68-1.53 (m, 2H), 0.91 (t, J=8.0 Hz, 3H).MS obsd. (ESI⁺) [(M+H)⁺]: 360.

Step 4: Preparation of4-[[6-[(4-methoxyphenyl)methylamino]-8-oxo-2-propylsulfanyl-7H-purin-9-yl]methyl]benzonitrile

Compound 32d was prepared in analogy to Example 15, Step 4 by using4-[(6-chloro-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzonitrile(compound 32c) instead of 6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15c).4-[[6-[(4-Methoxyphenyl)methylamino]-8-oxo-2-propylsulfanyl-7H-purin-9-yl]methyl]benzonitrile(3.0 g, compound 32d) was obtained as a light red solid. MS obsd. (ESI⁺)[(M+H)⁺]: 461.

Step 5: Preparation of4-[(6-amino-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzonitrile(compound 32e) and4-[(6-amino-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzamide(compound 33a)

Compound 32e, 33a were prepared in analogy to Example 15, Step 5 byusing 4-[[6-[(4-methoxyphenyl)methylamino]-8-oxo-2-propylsulfanyl-7H-purin-9-yl]methyl]benzonitrile (compound 32d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one (compound 15d).4-[(6-Amino-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzonitrile(compound 32e) and4-[(6-amino-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzamide(compound 33a) was obtained as a mixture (1.5 g).

Step 6: Preparation of4-[(6-amino-8-oxo-2-propylsulfinyl-7H-purin-9-yl)methyl]benzonitrile(compound 32f) and4-[(6-amino-8-oxo-2-propylsulfinyl-7H-purin-9-yl)methyl]benzamide(compound 33b)

Compound 32f, 33b were prepared in analogy to Example 15, Step 6 byusing the mixture of4-[(6-amino-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzonitrile(compound 32e) and4-[(6-amino-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzamide(compound 33a) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e).4-[(6-Amino-8-oxo-2-propylsulfinyl-7H-purin-9-yl)methyl]benzonitrile(compound 32f) and4-[(6-amino-8-oxo-2-propylsulfinyl-7H-purin-9-yl)methyl]benzamide (250mg, compound 33b) was obtained as a mixture of white solid.

Step 7: Preparation of4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzonitrile(compound 32) and4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzamide(compound 33)

The title compound was prepared in analogy to Example 15, Step 7 byusing the mixture of4-[(6-amino-8-oxo-2-propylsulfinyl-7H-purin-9-yl)methyl]benzonitrile(compound 32f) and4-[(6-amino-8-oxo-2-propylsulfinyl-7H-purin-9-yl)methyl]benzamide(compound 33b) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 15f). The residue was purified by prep-HPLC to give4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzonitrile(24.7 mg, Example 32) and4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzamide(18.8 mg, Example 33).

Example 32

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.82 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.0Hz, 2H), 7.04 (br. s., 2H), 5.06 (s, 2H), 4.02 (s, 1H), 3.29-3.26 (m,2H), 1.66-1.54 (m, 2H), 0.89 (t, J=8.0 Hz, 3H). MS obsd. (ESI⁺)[(M+H)⁺]: 372.

Example 33

¹H NMR (400 MHz DMSO-d₆) δ ppm: 10.73 (br. s., 1H), 7.94 (s, 1H), 7.82(d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.34 (s, 1H), 7.02 (br. s.,2H), 5.01 (s, 2H), 4.03 (s, 1H), 3.31-3.27 (m, 2H), 1.68-1.56 (m, 2H),0.90 (t, J=8.0 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 390.

Example 346-Amino-9-[(6-methyl-3-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of 6-methylpyridine-3-carbonitrile

To a suspension of 6-methylpyridine-3-carboxylic acid (17.0 g, 125 mmol)in toluene (200 mL) was added phosphoryl trichloride (84.24 g, 708 mmol)drop-wise. After the addition, the reaction mixture was stirred at 100°C. for 12 hrs. The mixture was cooled to RT and the solvent was removedin vacuo. The residue was suspended in EtOAc (400 mL), basified withsat. NaHCO₃ (400 mL), and extracted with EtOAc (300 mL) two times. Thecombined organic layer was dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluted with (PE/EtOAc from 10/1 to 5/1) togive 6-methylpyridine-3-carbonitrile (10.5 g, compound 34a) as a lightyellow solid. MS obsd. (ESI⁺) [(M+H)⁺]: 119.

Step 2: Preparation of (6-methyl-3-pyridyl)methylamine

To a solution of 6-methylpyridine-3-carbonitrile (10.5 g, 25.7 mmol) inMeOH (80 mL) and NH₃/MeOH (20 mL, 7 M) was added Raney-Ni (2.0 g) underN₂ atmosphere. The suspension was degassed in vacuo and refilled withH₂. The mixture was stirred for 12 hrs at 40° C. under H₂ (50 psi)atmosphere. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give (6-methyl-3-pyridyl)methyl amine (9.5 g,compound 34b) as a light oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.36 (s,1H), 7.62 (d, J=8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 3.69 (s, 2H), 2.42(s, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 123.

Step 3: Preparation of6-chloro-N-[(6-methyl-3-pyridyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 34c was prepared in analogy to Example 15, Step 1 by using(6-methyl-3-pyridyl)methylamine (compound 34b) instead of(2-chlorophenyl)methylamine.6-Chloro-N-[(6-methyl-3-pyridyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(15.5 mg, compound 34c) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 354.

Step 4: Preparation of6-chloro-N-4-[(6-methyl-3-pyridyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 34d was prepared in analogy to Example 15, Step 2 by using6-chloro-N-[(6-methyl-3-pyridyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 34c) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a). 6-Chloro-N-4-[(6-methyl-3-pyri dyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine (10.9 g, compound 34d) was obtained as awhite solid. MS obsd. (ESI⁺) [(M+H)⁺]: 324.

Step 5: Preparation of6-chloro-9-[(6-methyl-3-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 34e was prepared in analogy to Example 15, Step 3 by using6-chloro-N-4-[(6-methyl-3-pyridyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 34d) instead of6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b). 6-Chloro-9-[(6-methyl-3-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one (12.0 g, compound 34e) was obtained as a whitesolid. MS obsd. (ESI⁺) [(M+H)⁺]: 350.

Step 6: Preparation of6-[(4-methoxyphenyl)methylamino]-9-[(6-methyl-3-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 34f was prepared in analogy to Example 15, Step 4 by using6-chloro-9-[(6-methyl-3-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 34e) instead of 6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15c). 6-[(4-Methoxyphenyl)methylamino]-9-[(6-methyl-3-pyridyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(15.0 g, compound 34f) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 451.

Step 7: Preparation of6-amino-9-[(6-methyl-3-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 34g was prepared in analogy to Example 15, Step 5 by using6-[(4-methoxyphenyl)methylamino]-9-[(6-methyl-3-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 34f) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d).6-Amino-9-[(6-methyl-3-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one(7.9 g, compound 34g) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 331.

Step 8: Preparation of6-amino-9-[(6-methyl-3-pyridyl)methyl]-2-propylsulfinyl-7H-purin-8-one

Compound 34h was prepared in analogy to Example 15, Step 6 by using6-amino-9-[(6-methyl-3-pyridyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(compound 34g) instead6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e).6-Amino-9-[(6-methyl-3-pyridyl)methyl]-2-propylsulfinyl-7H-purin-8-one(300 mg, compound 34h) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 347.

Step 9: Preparation of6-amino-9-[(6-methyl-3-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing6-amino-9-[(6-methyl-3-pyridyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 34h) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 15f). 6-Amino-9-[(6-methyl-3-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one (13 mg, Example 34) was obtained as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ□ppm: 8.47 (s, 1H), 7.63 (dd,J=8.0 Hz, 2.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.07 (s, 2H), 4.95 (s,2H), 4.06 (s, 1H), 3.32-3.29 (m, 2H), 2.42 (s, 3H), 1.71-1.57 (m, 2H),0.92 (t, J=7.4 Hz, 3H) MS obsd. (ESI⁺) [(M+H)⁺]: 363.

Example 356-Amino-9-[(2-methyl-4-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of 2-methylpyridine-4-carbonitrile

A mixture of 2-chloropyridine-4-carbonitrile (30.0 g, 216.0 mol), AlMe₃(11 mL, 220 mmol, 2 Min toluene) and Pd(PPh₃)₄ (2.3 g, 2.0 mmol) indioxane (400 mL) was heated to 130° C. for 10 hrs under N₂ atmosphere.The mixture was cooled to RT, then poured into ice water (1000 mL),extracted with EtOAc. The combined organic layer was dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by column chromatography eluted with PE/EtOAc (2/1) to afford2-methylpyridine-4-carbonitrile (compound 35a) as a yellow crystal. (5.2g). ¹H NMR (400 MHz, DMSO-d₆) □ ppm: 8.68 (d, J=5.0 Hz, 1H), 7.39 (s,1H), 7.33 (d, J=5.0 Hz, 1H), 2.63 (s, 3H). MS obsd. (ESI⁺) [(M+H)⁺]:119.

Step 2: Preparation of (2-methyl-4-pyridyl)methylanamine

To a solution of 2-methylpyridine-4-carbonitrile (1.6 g, 13 mmol,compound 35a) in MeOH (30 mL) and NH₃/MeOH (20 mL, 7 M) was addedRaney-Ni (2.0 g) under N₂ atmosphere. The suspension was degassed invacuo and purged with H₂ two times. The mixture was stirred under H₂ (50psi) atmosphere at 40° C. for 12 hrs. The reaction mixture was thenfiltered and the filtrate was concentrated in vacuo to give(2-methyl-4-pyridyl)methylanamine ((1.6 g, compound 35b) as a brown oil.¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.41 (J=5.0 Hz, 1H), 7.12-7.04 (m, 2H),3.86 (s, 2H), 2.54 (s, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 123.

Step 3: Preparation of6-chloro-N-[(2-methyl-4-pyridyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 35c was prepared in analogy to Example 15, Step 1 by using(2-methyl-4-pyridyl)methylamine (compound 35b) instead of(2-chlorophenyl)methanamine.6-Chloro-N-[(2-methyl-4-pyridyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(4.3 g, compound 35c) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 354.

Step 4: Preparation of6-chloro-N4-[(2-methyl-4-pyridyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 35d was prepared in analogy to Example 15, Step 2 by6-chloro-N-[(2-methyl-4-pyridyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 35c) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine (compound 15a).6-Chloro-N-4-[(2-methyl-4-pyridyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(2.0 g, compound 35d) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 324.

Step 5: Preparation of6-chloro-9-[(2-methyl-4-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 35e was prepared in analogy to Example 15, Step 3 by using6-chloro-N4-[(2-methyl-4-pyridyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 35d) instead of6-chloro-N-4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b). 6-Chloro-9-[(2-methyl-4-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one (2.5 g, compound 35e) was obtained as a whitesolid. MS obsd. (ESI⁺) [(M+H)⁺]: 350.

Step 6: Preparation of6-[(4-methoxyphenyl)methylamino]-9-[(2-methyl-4-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 35f was prepared in analogy to Example 15, Step 4 by using6-chloro-9-[(2-methyl-4-pyridyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(compound 35e) instead of 6-chloro-9-[(2-methyl-4-pyridyl)methyl]-2-propyl sulfanyl-7H-purin-8-one (compound 15c).6-[(4-Methoxyphenyl)methylamino]-9-[(2-methyl-4-pyridyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(3.3 g, compound 35f) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 450.

Step 7: Preparation of6-amino-9-[(2-methyl-4-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 35g was prepared in analogy to Example 15, Step 5 by using6-[(4-methoxyphenyl)methylamino]-9-[(2-methyl-4-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 35f) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d).6-Amino-9-[(2-methyl-4-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 35g) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:331.

Step 8: Preparation of6-amino-9-[(2-methyl-4-pyridyl)methyl]-2-propylsulfinyl-7H-purin-8-one

Compound 35h was prepared in analogy to Example 15, Step 6 by using6-amino-9-[(2-methyl-4-pyridyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(compound 35g) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15e).6-Amino-9-[(2-methyl-4-pyridyl)methyl]-2-propylsulfinyl-7H-purin-8-one(180 mg, compound 35h) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 347.

Step 9: Preparation of6-amino-9-[(2-methyl-4-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 6-amino-9-[(2-methyl-4-pyridyl)methyl]-2-propylsulfinyl-7H-purin-8-one (compound 35h) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propyl sulfinyl-7H-purin-8-one(compound 15f). 6-Amino-2-(propylsulfonimidoyl)-9-[[(2,4-difluorophenyl)methyl]-7H-purin-8-one (21 mg,Example 35) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δppm: 10.68 (br. s., 1H), 7.56 (t, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H),7.24-7.14 (m, 1H), 7.01 (br. s., 2H), 4.98 (s, 2H), 4.05 (s, 1H),3.32-3.24 (m, 2H), 2.45 (s, 3H), 1.71-1.52 (m, 2H), 0.90 (t, J=8.0 Hz,3H). MS obsd. (ESI⁺) [(M+H)⁺]: 362.

Example 366-Amino-9-[(3-chloro-4-methyl-phenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-N-[(2,4-difluorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 36a was prepared in analogy to Example 15, Step 1 by using(3-chloro-4-methyl-phenyl)methylamine instead of(2-chlorophenyl)methylamine.6-Chloro-N-[(3-chloro-4-methyl-phenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(5.0 g, compound 36a) was obtained as a yellow solid. MS obsd. (ESI⁺)[(M+H)⁺]: 387.

Step 2: Preparation of6-chloro-N4-[(3-chloro-4-methyl-phenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 36b was prepared in analogy to Example 15, Step 2 by using6-chloro-N-[(3-chloro-4-methyl-phenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 36a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine (compound 15a).6-Chloro-N4-[(3-chloro-4-methyl-phenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine (4.0 g, compound 36b) was obtained as awhite solid. MS obsd. (ESI⁺) [(M+H)⁺]: 357.

Step 3: Preparation of6-chloro-9-[(3-chloro-4-methyl-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 36c was prepared in analogy to Example 15, Step 3 by using6-chloro-N4-[(3-chloro-4-methyl-phenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 36b) instead of6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b).6-Chloro-9-[(3-chloro-4-methyl-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 36c) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:383.

Step 4: Preparation of9-[(3-chloro-4-methyl-phenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one

Compound 36d was prepared in analogy to Example 15, Step 4 by using6-chloro-9-[(3-chloro-4-methyl-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 36c) instead of 6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15c).9-[(3-Chloro-4-methyl-phenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one (4.0 g, compound 36d) was obtained as a whitesolid. MS obsd. (ESI⁺) [(M+H)⁺]: 484.

Step 5: Preparation of6-amino-9-[(3-chloro-4-methyl-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 36e was prepared in analogy to Example 15, Step 5 by using9-[(3-chloro-4-methyl-phenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one (compound 36d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one.6-Amino-9-[(3-chloro-4-methyl-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(230 mg, compound 36e) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 364.

Step 6: Preparation of6-amino-9-[(3-chloro-4-methyl-phenyl)methyl]-2-propylsulfinyl-7H-purin-8-one

Compound 36f was prepared in analogy to Example 15, Step 6 by using6-amino-9-[(3-chloro-4-methyl-phenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 36e) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e).6-Amino-9-[(3-chloro-4-methyl-phenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(155 mg, compound 36f) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 380.

Step 7: Preparation of6-amino-9-[(3-chloro-4-methyl-phenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 6-amino-9-[(3-chloro-4-methyl-phenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (155 mg, compound 36f) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 15f).6-Amino-9-[(3-chloro-4-methyl-phenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one(34 mg, Example 36) was obtained as a gray solid. ¹H NMR (400 MHz,DMSO-d₆) δ□ppm: 7.39 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz,1H), 7.03 (br. s., 2H), 4.93 (s, 2H), 4.02 (s, 1H), 3.30-3.27 (m, 2H),1.72-1.54 (m, 2H), 0.91 (t, J=8.0 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]:395.

Example 376-Amino-9-[(4-methylsulfonylphenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-N-[(4-methylsulfonylphenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 37a was prepared in analogy to Example 15, Step 1 by using(4-methylsulfonylphenyl)methylamine instead of(2-chlorophenyl)methylamine.6-Chloro-N-[(4-methylsulfonylphenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(3.6 g, compound 37a) was obtained as a yellow solid. MS obsd. (ESI⁺)[(M+H)⁺]: 417.

Step 2: Preparation of6-chloro-N4-[(4-methylsulfonylphenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 37b was prepared in analogy to Example 15, Step 2 by using6-chloro-N-[(4-methylsulfonylphenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 37a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine (compound 15a).6-Chloro-N4-[(4-methylsulfonylphenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(3.2 g, compound 37b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 387.

Step 3: Preparation of6-chloro-9-[(4-methylsulfonylphenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 37c was prepared in analogy to Example 15, Step 3 by using6-chloro-N4-[(4-methylsulfonylphenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine (compound37b) instead of6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine (compound 15b). 6-Chloro-9-[(4-methylsulfonylphenyl)methyl]-2-propyl sulfanyl-7H-purin-8-one (2.0 g, compound37c) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 413.

Step 4: Preparation of6-[(4-methoxyphenyl)methylamino]-9-[(4-methylsulfonylphenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 37d was prepared in analogy to Example 15, Step 4 by using6-chloro-9-[(4-methyl sulfonylphenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 37c) instead of6-chloro-9-[(2-chlorophenyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(compound 15c).6-[(4-Methoxyphenyl)methylamino]-9-[(4-methylsulfonylphenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(2.2 g, compound 37d) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 514.

Step 5: Preparation of6-amino-9-[(4-methylsulfonylphenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 37e was prepared in analogy to Example 15, Step 5 by using6-[(4-methoxyphenyl)methylamino]-9-[(4-methylsulfonylphenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 36d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one.6-Amino-9-[(4-methylsulfonylphenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(1.2 g, compound 37e) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 394.

Step 6: Preparation of6-amino-9-[(4-methylsulfonylphenyl)methyl]-2-propylsulfinyl-7H-purin-8-one

Compound 37d was prepared in analogy to Example 15, Step 6 by using6-amino-9-[(4-methylsulfonylphenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 37e)instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e).6-Amino-9-[(4-methylsulfonylphenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(200 mg, compound 37f) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 410.

Step 7: Preparation of6-amino-2-(propylsulfonimidoyl)-9-[[(2,4-difluorophenyl)methyl]-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 6-amino-9-[(4-methyl sulfonylphenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (compound 37f) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 15f). 6-Amino-9-[(4-methyl sulfonylphenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one (17 mg, Example 37) was obtained as a graysolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.89 (d, J=8.0 Hz, 2H), 7.57 (d,J=8.0 Hz, 2H), 7.11 (br. s., 2H), 5.08 (s, 2H), 4.07 (s, 1H), 3.34-3.28(m, 2H), 3.18 (s, 3H), 1.65-1.57 (m, 2H), 0.89 (t, J=8.0 Hz, 3H). MSobsd. (ESI⁺) [(M+H)⁺]: 425.

Example 38 Methyl4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzoate

Step 1: Preparation of methyl4-[[(6-chloro-5-nitro-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzoate

Compound 38a was prepared in analogy to Example 15, Step 1 by usingmethyl 4-(aminomethyl)benzoate instead of (2-chlorophenyl)methylamine.Methyl4-[[(6-chloro-5-nitro-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzoate(compound 38a) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:397.

Step 2: Preparation of methyl4-[[(6-chloro-5-methyl-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzoate

Compound 38b was prepared in analogy to Example 15, Step 2 by usingmethyl4-[[(6-chloro-5-nitro-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzoate(compound 38a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a). Methyl4-[[(6-chloro-5-methyl-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzoate(compound 38b) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:366.

Step 3: Preparation of methyl4-[(6-chloro-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzoate

Compound 38c was prepared in analogy to Example 15, Step 3 by usingmethyl4-[[(6-chloro-5-methyl-2-propylsulfanyl-pyrimidin-4-yl)amino]methyl]benzoate(compound 38b) instead of6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b). Methyl4-[(6-chloro-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzoate(compound 38c) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:39.

Step 4: Preparation of methyl4-[[6-[(4-methoxyphenyl)methylamino]-8-oxo-2-propylsulfanyl-7H-purin-9-yl]methyl]benzoate

Compound 38d was prepared in analogy to Example 15, Step 4 by usingmethyl 4-[(6-chloro-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzoate(compound 38c) instead of6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15c). Methyl4-[[6-[(4-methoxyphenyl)methylamino]-8-oxo-2-propylsulfanyl-7H-purin-9-yl]methyl]benzoate(compound 38d) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:494.

Step 5: Preparation of methyl4-[(6-amino-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzoate

Compound 38e was prepared in analogy to Example 15, Step 5 by usingmethyl4-[[6-[(4-methoxyphenyl)methylamino]-8-oxo-2-propylsulfanyl-7H-purin-9-yl]methyl]benzoate(compound 38d) instead of9-[(2-chlorophenyl)methyl]-6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-7H-purin-8-one(compound 15d). Methyl4-[(6-amino-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzoate(compound 38e) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:374.

Step 6: Preparation of methyl4-[(6-amino-8-oxo-2-propylsulfinyl-7H-purin-9-yl)methyl]benzoate

Compound 38f was prepared in analogy to Example 15, Step 6 by usingmethyl 4-[(6-amino-8-oxo-2-propylsulfanyl-7H-purin-9-yl)methyl]benzoate(compound 38e) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e). Methyl4-[(6-amino-8-oxo-2-propylsulfinyl-7H-purin-9-yl)methyl]benzoate(compound 38f) was obtained as a white solid MS obsd. (ESI⁺) [(M+H)⁺]:390.

Step 7: Preparation of methyl4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzoate

The title compound was prepared in analogy to Example 15, Step 7 byusing methyl4-[(6-amino-8-oxo-2-propylsulfinyl-7H-purin-9-yl)methyl]benzoate(compound 38f) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one. Methyl4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzoate(127 mg, Example 38) was obtained as a white solid. ¹H NMR (400 MHzDMSO-d₆) δ ppm: 10.75 (br. s., 1H), 7.92 (d, J=8.0 Hz, 2H), 7.45 (d,J=8.0 Hz, 2H), 6.99 (br. s., 2H), 5.05 (s, 2H), 4.00 (s, 1H), 3.84 (s,3H), 3.32-3.27 (m, 2H), 1.64-1.56 (m, 2H), 0.88 (t, J=8.0 Hz, 3H). MSobsd. (ESI⁺) [(M+H)⁺]: 405.

Example 394-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzoicacid

To a solution of methyl4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzoate(70 mg, compound 38) in THF/MeOH (2/1, V/V, 3 mL) was added aqueous LiOH(0.34 mL, 0.34 mmol, 1M) and the mixture was stirred at 25° C. for 3hrs. Then the reaction mixture was acidified by the addition of 1N HCl.The formed solid was collected by filtration and purified by prep-HPLCto give4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzoicacid (38 mg, Example 39). ¹H NMR (400 MHz DMSO-d₆) δ ppm: 10.76 (br. s.,1H), 7.89 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 7.03 (br. s., 2H),5.04 (s, 2H), 4.05 (s, 1H), 3.32-3.27 (m, 2H), 1.63-1.55 (m, 2H), 0.88(t, J=8.0 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 391.

Example 404-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]-N-(2-methoxyethyl)benzamide

To a solution of4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzoicacid (100 mg, compound 39), HATU (146 mg, 0.38 mmol) and anhydrous DIPEA(89 μL, 0.51 mmol) in anhydrous DMF (5 mL) was added 2-methoxyethanamine(44 μL, 0.51 mmol). The reaction mixture was stirred at rt overnight andthen evaporated in vacuo. The residue was purified by Prep-HPLC to give4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]-N-(2-methoxyethyl)benzamide(18 mg, Example 40) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm:10.59 (s, 1H), 8.44-8.61 (m, 1H), 7.80 (d, J=7.50 Hz, 2H), 7.40 (d,J=7.49 Hz, 2H), 6.98 (br. s., 2H), 5.01 (s, 2H), 4.04 (br. s., 1H),3.38-3.44 (m, 4H), 3.29-3.30 (m, 2H), 3.25 (s, 3H), 1.58-1.66 (m, 2H),0.91 (t, J=7.53 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 448

Example 416-Amino-9-[[4-(piperidine-1-carbonyl)phenyl]methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 40 by usingpiperidine instead of 2-methoxyethanamine.6-Amino-9-[[4-(piperidine-1-carbonyl)phenyl]methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one(6.5 mg, Example 41) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 10.80 (s, 1H), 7.31-7.39 (m, 4H), 7.04 (br. s., 2H),5.00 (s, 2H), 4.03 (s, 1H), 3.55 (br. s., 2H), 3.26-3.39 (m, 4H),1.43-1.68 (m, 8H), 0.93 (t, J=7.40 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]:458.

Example 426-Amino-2-(propylsulfonimidoyl)-9-[[4-(pyrrolidine-1-carbonyl)phenyl]methyl]-7H-purin-8-one

The title compound was prepared in analogy to Example 40 by usingpyrrolidine instead of 2-methoxyethanamine.6-Amino-2-(propylsulfonimidoyl)-9-[[4-(pyrrolidine-1-carbonyl)phenyl]methyl]-7H-purin-8-one(8.0 mg, Example 42) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 10.60 (s, 1H), 7.48 (d, J=7.31 Hz, 2H), 7.37 (d, J=8.03Hz, 2H), 6.99 (br. s., 2H), 5.00 (s, 2H), 4.10 (s, 1H), 3.40-3.46 (m,2H), 3.31-3.34 (m, 4H), 1.62-1.67 (m, 4H), 1.62-1.67 (m, 2H), 0.91 (t,J=7.40 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 444

Example 436-Amino-2-(propylsulfonimidoyl)-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-5-nitro-2-propylsulfanyl-N-(pyrimidin-5-ylmethyl)pyrimidin-4-amine

Compound 43a was prepared in analogy to Example 15, Step 1 by using4,6-dichloro-5-nitro-2-(propylthio)pyrimidine instead of(2-chlorophenyl)methylamine.6-Chloro-5-nitro-2-(propylthio)-N-(pyrimidin-5-ylmethyl)-pyrimidin-4-amine(4.0 g, compound 43a) was obtained as a light yellow oil. MS obsd.(ESI⁺) [(M+H)⁺]: 341.

Step 2: Preparation of6-chloro-2-propylsulfanyl-N4-(pyrimidin-5-ylmethyl)pyrimidine-4,5-diamine

Compound 43b was prepared in analogy to Example 15, Step 2 by using6-chloro-5-nitro-2-(propylthio)-N-(pyrimidin-5-ylmethyl)pyrimidin-4-amine (compound 43a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).6-Chloro-2-propylsulfanyl-N4-(pyrimidin-5-ylmethyl)pyrimidine-4,5-diamine(1.0 g, compound 43b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 311.

Step 3: Preparation of6-chloro-2-propylsulfanyl-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one

Compound 43c was prepared in analogy to Example 15, Step 3 by using6-Chloro-2-propylsulfanyl-N4-(pyrimidin-5-ylmethyl)pyrimidine-4,5-diamine(compound 43b) instead of6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b). 6-Chloro-2-propylsulfanyl-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one (0.5 g, compound 43c)was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 337.

Step 4: Preparation of6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one

Compound 43d was prepared in analogy to Example 15, Step 4 by using6-chloro-2-propylsulfanyl-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one(compound 43c) instead of6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15c). 6-[(4-Methoxyphenyl)methyl amino]-2-propylsulfanyl-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one (300 mg, compound 43d)was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 438.

Step 5: Preparation of6-[(4-methoxyphenyl)methylamino]-2-propylsulfinyl-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one

Compound 43e was prepared in analogy to Example 15, Step 6 by using6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one (compound 43d) insteadof 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e). 6-[(4-Methoxyphenyl)methyl amino]-2-propylsulfinyl-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one (280 mg, compound 43e)was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 454.

Step 6: Preparation of6-amino-2-(propylsulfonimidoyl)-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing6-[(4-methoxyphenyl)methylamino]-2-propylsulfinyl-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one(compound 43e) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (compound 15f).6-Amino-2-(propylsulfonimidoyl)-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one(70 mg, Example 43) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) ppm: 9.13 (s, 1H), 8.83 (s, 2H), 7.07 (br. s., 2H), 5.04 (s,2H), 4.08 (s, 1H), 3.27-3.34 (m, 2H), 1.50-1.69 (m, 2H), 0.92 (t, J=7.2Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 349.

Example 446-Amino-9-[(2-methylpyrimidin-5-yl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation ofN,N′-[2-[1-(dimethylamino)methylidene]propane-1,3-diylidene]bis(N-methylmethanaminium)bis(tetrafluoroborate)

To cooled DMF (400 mL) in a round-bottomed flask was added POCl₃ (165.5g) at −10° C. The reaction mixture was stirred at 0° C. for 3 hrs. Tothis reaction mixture was added 2-bromoacetic acid (50 g, 360 mmol) at0° C. The resulting reaction mixture was stirred at 80° C. for 16 hrs,then DMF was removed in vacuo. The dark red residue was cooled down toroom temperature and sodium tetrafluoroborate (100 g, 911 mmol) wasadded into the residue. After the reaction mixture was cooled in icebath,N,N′-[2-[1-(dimethylamino)methylidene]propane-1,3-diylidene]bis(N-methylmethanaminium)bis(tetrafluoroborate) (120 g, compound 44a) was obtained by filtrationas a brown solid and used in next step without purification.

Step 2: Preparation of 2-methylpyrimidine-5-carbaldehyde

To a mixture ofN,N′-[2-[1-(dimethylamino)methylidene]propane-1,3-diylidene]bis(N-methylmethanaminium)bis(tetrafluoroborate) (70 g, 196 mmol, compound 44a) and acetamidineHCl (37 g, 392 mmol) in MeCN/H₂O (400 mL, V/V=1/1) was added NaOH (120g, 3.0 mmol) at 15° C., and the resulting reaction mixture was stirredat 15° C. for 16 hrs. The reaction mixture was neutralized to pH 6-7with AcOH, extracted by ethyl acetate (100 mL) three times. Theseparated organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyto afford 2-methylpyrimidine-5-carbaldehyde (10 g, compound 44b) as ayellow solid.

Step 3: Preparation of (2-methylpyrimidin-5-yl)methanol

To a mixture of 2-methylpyrimidine-5-carbaldehyde (8 g, 66 mmol,compound 44b) in MeOH (100 mL) was added NaBH₄ (7.5 g, 197 mmol) at 0°C., and the resulting reaction mixture was stirred at 15° C. for 3 hrs.Then the reaction mixture was quenched by saturated NH₄Cl solution (30mL), extracted by ethyl acetate (20 mL) three times. The separatedorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo. The residue was purified by column chromatography to afford(2-methylpyrimidin-5-yl)methanol (4.1 g, 51%, compound 44c) as a whitesolid.

Step 4: Preparation of 5-(azidomethyl)-2-methylpyrimidine

To a mixture of (2-methylpyrimidin-5-yl)methanol (4.1 g, 33 mmol,compound 44c) in CHCl₃ (40 mL) and toluene (40 mL) was added DPPA (27 g,83 mmol) and DBU (25 g, 164 mmol) at 0° C. and stirred at 15° C. for 16hrs. The reaction mixture was diluted with DCM (100 mL) and washed withwater (50 mL). The separated organic layer was dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography to afford crude5-(azidomethyl)-2-methylpyrimidine (2.8 g, compound 44d) as a light oil.

Step 5: Preparation of (2-methylpyrimidin-5-yl)methanamine

A mixture of 5-(azidomethyl)-2-methylpyrimidine (2.8 g, 18.8 mmol,compound 44d) and Pd/C (500 mg) in MeOH (100 mL) was stirred under 1 atmof H₂ atmosphere at 15° C. for 1 hour. Then the reaction mixture wasfiltered, and the filtrate was concentrated in vacuo to afford(2-methylpyrimidin-5-yl)methanamine (1.8 g, 78%, compound 44e) as awhite solid.

Step 6:6-Chloro-N4-[(2-methylpyrimidin-5-yl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 44f was prepared in analogy to Example 15, Step 1 by using(2-methylpyrimidin-5-yl)methanamine (compound 44e) instead of(2-chlorophenyl)methylamine.6-Chloro-N4-[(2-methylpyrimidin-5-yl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(2.8 g, compound 44f) was obtained as a light yellow oil. MS obsd.(ESI⁺) [(M+H)⁺]: 355.

Step 7: Preparation of6-chloro-N4-[(2-methylpyrimidin-5-yl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 44g was prepared in analogy to Example 15, Step 2 by using6-chloro-N4-[(2-methylpyrimidin-5-yl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 44f) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).6-Chloro-N4-[(2-methylpyrimidin-5-yl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(2.1 g, compound 44g) was obtained and used in the next step withoutfurther purification. MS obsd. (ESI⁺) [(M+H)⁺]: 325.

Step 8: Preparation of6-chloro-9-[(2-methylpyrimidin-5-yl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 44h was prepared in analogy to Example 15, Step 3 by using6-chloro-N4-[(2-methylpyrimidin-5-yl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 44g) instead of 6-chloro-N4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine (compound 15b).6-Chloro-9-[(2-methylpyrimidin-5-yl)methyl]-2-propylsulfanyl-7H-purin-8-one (1.8 g, compound 44h) was obtained as a whitesolid. MS obsd. (ESI⁺) [(M+H)⁺]: 351.

Step 9: Preparation of6-[(4-methoxyphenyl)methylamino]-9-[(2-methylpyrimidin-5-yl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 44i was prepared in analogy to Example 15, Step 4 by using6-chloro-9-[(2-methylpyrimidin-5-yl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 44h) instead of 6-chloro-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (compound 15c). 6-[(4-Methoxyphenyl)methylamino]-2-propyl sulfanyl-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one (500mg, compound 44i) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 452.

Step 10: Preparation of6-[(4-methoxyphenyl)methylamino]-9-[(2-methylpyrimidin-5-yl)methyl]-2-propylsulfinyl-7H-purin-8-one

Compound 44j was prepared in analogy to Example 15, Step 6 by using6-[(4-methoxyphenyl)methylamino]-2-propylsulfanyl-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one(compound 43i) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e). 6-[(4-Methoxyphenyl)methylamino]-9-[(2-methylpyrimidin-5-yl)methyl]-2-propylsulfinyl-7H-purin-8-one(420 mg, compound 44j) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 468.

Step 11: Preparation of6-amino-9-[(2-methylpyrimidin-5-yl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing6-[(4-methoxyphenyl)methylamino]-9-[(2-methylpyrimidin-5-yl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 44j) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 15f). 6-Amino-9-[(2-methylpyrimidin-5-yl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one (16.5 mg, Example 44) was obtained as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.71 (s, 2H), 6.98 (s,2H), 4.99 (s, 2H), 4.10 (s, 1H), 3.35 (m, 2H), 2.59 (s, 3H), 1.65-1.62(m, 2H), 0.95-0.91 (t, J=7.2 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 363.

Example 46

-   N-[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]pentanamide

To the solution of 6-amino-9-benzyl-2-(propylsulfonimidoyl)-7H-purin-8-one (70 mg, 0.21 mmol, compound 4) in pyridine(2 mL) was added valeric acid anhydride (41 mg, 0.22 mmol). The reactionmixture was stirred at RT for 6 hrs. After reaction, the solvent wasremoved in vacuo. The residue was purified by prep-HPLC to giveN-[(6-amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]pentanamide(13.7 mg, Example 46). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.29-7.32 (m,5H), 7.19 (br. s., 2H), 4.90 (m, 2H), 3.48-3.50 (m, 2H), 2.17 (t, J=7.2Hz, 2H), 1.50-1.70 (m, 2H), 1.39-1.47 (m, 2H), 1.61-1.76 (m, 1H),1.47-1.59 (m, 1H), 0.89 (t, J=7.40 Hz, 3H), 0.80 (t, J=7.39 Hz, 3H). MSobsd. (ESI⁺) [(M+H)⁺]: 431.

Example 47N-[[6-Amino-9-[(4-chlorophenyl)methyl]-8-oxo-7H-purin-2-yl]-oxo-propyl-λ⁴-sulfanylidene]acetamide

The title compound was prepared in analogy to Example 46 by using aceticanhydride and 6-amino-9-(4-chlorobenzylmethyl)-2-(propylsulfonimidoyl)-7H-purin-8-one (compound 9) instead of valeric acidanhydride and 6-amino-9-benzyl-2-(propyl sulfonimidoyl)-7H-purin-8-one(Example 4).N-[[6-Amino-9-[(4-chlorophenyl)methyl]-8-oxo-7H-purin-2-yl]-oxo-propyl-λ⁴-sulfanylidene]acetamide(2 mg, Example 47) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 7.31-7.40 (m, 4H), 7.29 (br. s., 2H), 4.95 (s, 2H),3.42-3.57 (m, 2H), 1.90 (s, 3H), 1.61-1.76 (m, 1H), 1.47-1.59 (m, 1H),0.89 (t, J=7.40 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 423.

Example 48N-[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-methyl-oxo-λ⁴-sulfanylidene]acetamide

The title compound was prepared in analogy to Example 46 by using aceticanhydride instead of valeric acid anhydride.N-[(6-amino-9-benzyl-8-oxo-7H-purin-2-yl)-methyl-oxo-λ⁴-sulfanylidene]acetamide(44 mg, Example 48) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 10.80 (br. s., 1H), 7.26-7.36 (m, 5H), 7.18 (br. s.,2H), 4.96 (s, 2H), 3.39 (s, 3H), 1.91 (s, 3H). MS obsd. (ESI⁺) [(M+H)⁺]:361.

Example 494-[[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]amino]-4-oxo-butanoicacid

The title compound was prepared in analogy to Example 46 by usingsuccinic anhydride instead of valeric acid anhydride.4-[[[6-Amino-9-[(4-chlorophenyl)methyl]-8-oxo-7H-purin-2-yl]-oxo-propyl-λ⁴-sulfanylidene]amino]-4-oxo-butanoicacid (500 mg, Example 49) was obtained as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm: 7.31-7.41 (m, 5H), 7.21 (br. s., 2H), 4.88-5.00 (m,2H), 3.40-3.64 (m, 2H), 2.41-2.46 (m, 2H), 2.30-2.36 (m, 2H), 1.56-1.66(m, 2H), 0.89 (t, J=7.4 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 481.

Separation of compound of Example 49 by chiral HPLC afforded Example49-A (faster eluting, 105 mg) and Example 49-B (slower eluting, 106.1mg) as white solid. (Separation condition: methanol 5%-40% (0.05%DEA)/CO₂ on ChiralPak IC-3 column.)

Example 49-A

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.40 (m, 2H), 7.27-7.30 (m, 5H), 4.95(s, 2H), 3.44-3.55 (m, 2H), 2.42-2.45 (m, 2H), 2.28-2.32 (m, 2H),1.55-1.69 (m, 2H), 0.87-0.910.87 (t, J=7.8 Hz, 3H). MS obsd. (ESI⁺)[(M+H)⁺]: 481

Example 49-B

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.46 (s, 2H), 7.26-7.32 (m, 5H), 4.95(s, 2H), 3.48-3.53 (m, 2H), 2.42-2.45 (m, 2H), 2.28-2.31 (m, 2H),1.55-1.69 (m, 2H), 0.87-0.90 (t, J=7.8 Hz, 3H). MS obsd. (ESI⁺)[(M+H)⁺]: 481

Example 50 Ethyl4-[[(6-amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]amino]-4-oxo-butanoate

The title compound was prepared in analogy to Example 46 by using ethyl4-chloro-4-oxo-butanoate instead of valeric acid anhydride.N-[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]benzamide(30 mg, Example 50) was obtained as a white solid.

Separation of compound of Example 50 by chiral HPLC afforded Example50-A (faster eluting, 11 mg) and Example 50-B (slower eluting, 12 mg) aswhite solid. (Separation condition: methanol 5%-40% (0.05% DEA)/CO₂ onChiralPak OD-3 column.)

Example 50-A

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.28-7.35 (m, 5H), 7.22 (br. s., 2H),4.94 (s, 2H), 3.98-4.03 (m, 2H), 3.48-3.51 (m, 2H), 2.33-2.40 (m, 4H),1.55-1.69 (m, 2H), 1.14 (t, J=7.2 Hz, 3H), 0.90 (t, J=7.6 Hz, 3H). MSobsd. (ESI⁺) [(M+H)⁺]: 475.

Example 50-B

¹H NMR (400 MHz, DMSO-d₆) δ□ppm: 7.28-7.35 (m, 5H), 7.22 (br. s., 2H),4.94 (s, 2H), 3.98-4.03 (m, 2H), 3.48-3.51 (m, 2H), 2.33-2.40 (m, 4H),1.55-1.69 (m, 2H), 1.14 (t, J=7.2 Hz, 3H), 0.90 (t, J=7.6 Hz, 3H). MSobsd. (ESI⁺) [(M+H)⁺]: 475.

Example 51N-[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]benzamide

The title compound was prepared in analogy to Example 46 by usingbenzoyl benzoate instead of valeric acid anhydride.N-[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]benzamide(220 mg, Example 51) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 10.77 (br.s., 1H), 8.08-7.89 (m, 2H), 7.61-7.41 (m, 3H),7.31-7.07 (m, 7H), 4.88 (d, J=3.8 Hz, 2H), 3.72-3.56 (m, 2H), 1.84-1.61(m, 2H), 0.97 (t, J=7.8 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 451.

Separation of compound of Example 51 by chiral HPLC afforded Example51-A (faster eluting, 50 mg) and Example 51-B (slower eluting, 50.5 mg)as white solid. (Separation condition: methanol 5%-40% (0.05% DEA)/CO₂on ChiralPak OD-3S column.)

Example 51-A

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.77 (br. s., 1H), 7.89-8.08 (m, 2H),7.41-7.61 (m, 3H), 7.07-7.31 (m, 7H), 4.88 (d, J=3.8 Hz, 2H), 3.56-3.72(m, 2H), 1.61-1.84 (m, 2H), 0.97 (t, J=7.8 Hz, 3H). MS obsd. (ESI⁺)[(M+H)⁺]: 451.

Example 51-B

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.78 (br. s., 1H), 7.94-8.05 (m, 2H),7.42-7.62 (m, 3H), 7.07-7.31 (m, 7H), 4.88 (d, J=3.8 Hz, 2H), 3.60-3.73(m, 2H), 1.61-1.90 (m, 2H), 0.97 (t, J=7.8 Hz, 3H). MS obsd. (ESI⁺)[(M+H)⁺]: 451.

Example 529-Benzyl-6-(ethylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation ofN-benzyl-6-chloro-5-nitro-2-(propylthio)pyrimidin-4-amine

Compound 52a was prepared in analogy to Example 15, Step 1 by usingbenzylamine instead of (2-chlorophenyl)methylamine.N-Benzyl-6-chloro-5-nitro-2-(propylthio)pyrimidin-4-amine (35 g,compound 52a) was obtained as a yellow solid. MS obsd. (ESI⁺) [(M+H)⁺]:339.

Step 2: Preparation ofN4-benzyl-6-chloro-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 52b was prepared in analogy to Example 15, Step 2 by usingN-benzyl-6-chloro-5-nitro-2-(propylthio)pyrimidin-4-amine (compound 52a)instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).N4-benzyl-6-chloro-2-propylsulfanyl-pyrimidine-4,5-diamine (28.0 g,compound 52b) was obtained as a brown solid. MS obsd. (ESI⁺) [(M+H)⁺]:309.

Step 3: Preparation of 9-benzyl-6-chloro-2-propylsulfanyl-7H-purin-8-one

Compound 52c was prepared in analogy to Example 15, Step 3 by usingN4-benzyl-6-chloro-2-propylsulfanyl-pyrimidine-4,5-diamine (compound52b) instead of6-chloro-N-4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b). 9-Benzyl-6-chloro-2-propylsulfanyl-7H-purin-8-one (24.0g, compound 52c) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 335.

Step 4: Preparation of9-benzyl-6-(ethylamino)-2-propylsulfanyl-7H-purin-8-one

To a solution of 9-benzyl-6-chloro-2-propylsulfanyl-7H-purin-8-one (2.3g, 6.9 mmol, compound 52c) in n-BuOH (8 mL) was added EtNH₂.HCl (1.7 g,20.6 mmol) and N-ethyl-N-isopropylpropan-2-amine (5.4 g, 41.4 mmol). Thereaction vessel was sealed and heated in microwave at 130° C. for 2 hrs.The solvent was removed in vacuo. The residue was suspended in EtOAc (20mL), washed with water (15 mL) two times and brine (30 mL). Theseparated organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo to give9-benzyl-6-(ethylamino)-2-propylsulfanyl-7H-purin-8-one (1.2 g, compound52d) as light yellow solid. MS obsd. (ESI⁺) [(M+H)⁺]: 344

Step 5: Preparation of9-benzyl-6-(ethylamino)-2-propylsulfinyl-7H-purin-8-one

To a solution of 9-benzyl-6-(ethylamino)-2-propylsulfanyl-7H-purin-8-one (682 mg, 2.0 mmol, compound 51d) in THF (8 mL)was added m-CPBA (415 mg, 2.4 mmol) in THF (2 mL) at 0° C. under N₂atmosphere. After the addition, the mixture was stirred at thistemperature for 30 min until a clear solution was formed. The reactionwas quenched by the addition of saturated Na₂SO₃ (5 mL), extracted withi-PrOH/DCM (20 mL, V/V=1/3) two times. The combined organic layer wasdried over Na₂SO₄ and concentrated to give9-benzyl-6-(ethylamino)-2-propylsulfinyl-7H-purin-8-one (580 mg,compound 52e) as light yellow solid. MS obsd. (ESI⁺) [(M+H)⁺]: 360.

Step 6: Preparation of9-benzyl-6-(ethylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 9-benzyl-6-(ethylamino)-2-propylsulfinyl-7H-purin-8-one (280 mg,compound 52e) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (compound 15f).9-Benzyl-6-(ethylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one (94 mg,Example 52) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δppm: 10.65 (s, 1H), 7.50-7.22 (m, 5H), 7.14-6.97 (m, 1H), 4.97 (s, 2H),4.07 (s, 1H), 3.58-3.44 (m, 2H), 3.36-3.28 (m, 2H), 1.78-1.54 (m, 2H),1.21 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.2 Hz, 3H). MS obsd. (ESI⁺)[(M+H)⁺]: 375.

Example 536-(Ethylamino)-9-[(6-methyl-3-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-(ethylamino)-9-[(6-methyl-3-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 53a was prepared in analogy to Example 52, Step 4 by using6-chloro-9-[(6-methyl-3-pyridyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(compound 34e) instead of9-benzyl-6-chloro-2-propylsulfanyl-7H-purin-8-one (compound 52c).6-(Ethylamino)-9-[(6-methyl-3-pyridyl)methyl]-2-propylsulfanyl-7H-purin-8-one(810 mg, compound 53a) was obtained as light yellow solid. MS obsd.(ESI⁺) [(M+H)⁺]: 359.

Step 2: Preparation of6-(ethylamino)-9-[(6-methyl-3-pyridyl)methyl]-2-propylsulfinyl-7H-purin-8-one

Compound 53b was prepared in analogy to Example 52, Step 5 by using6-chloro-9-[(6-methyl-3-pyridyl)methyl]-2-propyl sulfanyl-7H-purin-8-one(compound 53a) instead of9-benzyl-6-chloro-2-propylsulfanyl-7H-purin-8-one (compound 52d).6-(Ethylamino)-9-[(6-methyl-3-pyridyl)methyl]-2-propylsulfinyl-7H-purin-8-one(380 mg, compound 53b) was obtained as light yellow solid. MS obsd.(ESI⁺) [(M+H)⁺]: 375.

Step 3: Preparation of6-(ethylamino)-9-[(6-methyl-3-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 6-(ethylamino)-9-[(6-methyl-3-pyri dyl)methyl]-2-propylsulfinyl-7H-purin-8-one (280 mg, compound 53b) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 15f). 6-(Ethylamino)-9-[(6-methyl-3-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one (78 mg, Example 53) was obtained as lightyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.56 (s, 1H), 8.47 (s,1H), 7.62-7.64 (dd, J=8.0, 2.4 Hz, 1H), 7.20-7.22 (d, J=8.0 Hz, 1H),7.00 (m, 1H), 4.95 (s, 2H), 4.21 (s, 1H), 3.50-3.45 (m, 2H), 3.39-3.35(m, 2H), 2.42 (s, 3H), 1.61-1.71 (m, 2H), 1.18-1.21 (t, J=7.2 Hz, 3H),0.95-0.95 (t, J=7.2 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 390.

Example 549-[(4-Chlorophenyl)methyl]-6-(ethylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-chloro-N-[(4-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine

Compound 54a was prepared in analogy to Example 15, Step 1 by using(4-Chlorophenyl)methylamine instead of (2-chlorophenyl)methyl amine.6-Chloro-N-[(4-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(11 g, compound 54a) was obtained as a yellow solid. MS obsd. (ESI⁺)[(M+H)⁺]: 373.

Step 2: Preparation of6-chloro-N4-[(4-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine

Compound 54b was prepared in analogy to Example 15, Step 2 by usingN-4-chlorobenzyl-6-chloro-5-nitro-2-(propylthio)pyrimidin-4-amine(compound 54a) instead of6-chloro-N-[(2-chlorophenyl)methyl]-5-nitro-2-propylsulfanyl-pyrimidin-4-amine(compound 15a).6-chloro-N4-[(4-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(4.8 g, compound 54b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 343.

Step 3: Preparation of6-chloro-9-[(4-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one

Compound 54c was prepared in analogy to Example 15, Step 3 by using6-chloro-N4-[(4-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 54b) instead of6-chloro-N-4-[(2-chlorophenyl)methyl]-2-propylsulfanyl-pyrimidine-4,5-diamine(compound 15b). 6-Chloro-9-[(4-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one (4.5 g, compound 54c) was obtained as a whitesolid. MS obsd. (ESI⁺) [(M+H)⁺]: 369.

Step 4: Preparation of9-[(4-chlorophenyl)methyl]-6-(ethylamino)-2-propylsulfanyl-7H-purin-8-one

Compound 54d was prepared in analogy to Example 52, Step 4 by using6-chloro-9-[(4-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 54c) instead of9-benzyl-6-chloro-2-propylsulfanyl-7H-purin-8-one (compound 52c).9-[(4-Chlorophenyl)methyl]-6-(ethylamino)-2-propylsulfanyl-7H-purin-8-one(400 mg, compound 54d) was obtained as light yellow solid. MS obsd.(ESI⁺) [(M+H)⁺]: 378.

Step 5: Preparation of9-[(4-chlorophenyl)methyl]-6-(ethylamino)-2-propylsulfinyl-7H-purin-8-one

Compound 54e was prepared in analogy to Example 52, Step 5 by using9-[(4-chlorophenyl)methyl]-6-(ethylamino)-2-propylsulfanyl-7H-purin-8-one (compound 54d) instead of9-benzyl-6-chloro-2-propyl sulfanyl-7H-purin-8-one (compound 52d).9-[(4-Chlorophenyl)methyl]-6-(ethylamino)-2-propylsulfinyl-7H-purin-8-one(300 mg, compound 54e) was obtained as light yellow solid. MS obsd.(ESI⁺) [(M+H)⁺]: 394.

Step 6: Preparation of9-[(4-chlorophenyl)methyl]-6-(ethylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing9-[(4-chlorophenyl)methyl]-6-(ethylamino)-2-propylsulfinyl-7H-purin-8-one(compound 54e) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 15e).9-[(4-Chlorophenyl)methyl]-6-(ethylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one(86 mg, Example 54) was obtained as light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ□ppm: 10.50 (s, 1H), 7.31-7.42 (m, 3H), 6.97 (t, J=5.4 Hz,1H), 4.96 (s, 2H), 4.18 (s, 1H), 3.42-3.59 (m, 2H), 3.30-3.39 (m, 2H),1.54-1.76 (m, 2H), 1.15-1.28 (m, 3H), 0.86-0.99 (m, 3H). MS obsd. (ESI⁺)[(M+H)⁺]: 409.

Example 559-Benzyl-6-(propylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of9-benzyl-6-(propylamino)-2-propylsulfanyl-7H-purin-8-one

Compound 55a was prepared in analogy to Example 52, Step 4 by usingpropan-1-amine instead of EtNH₂.HCl. 9-Benzyl-6-(propyl amino)-2-propylsulfanyl-7H-purin-8-one (820 mg, compound 55a) was obtained as a whitesolid. MS obsd. (ESI⁺) [(M+H)⁺]: 358.

Step 2: Preparation of9-benzyl-6-(propylamino)-2-propylsulfinyl-7H-purin-8-one

Compound 55b was prepared in analogy to Example 52, Step 5 by using9-benzyl-6-(propylamino)-2-propyl sulfanyl-7H-purin-8-one (compound 55a)instead of 9-benzyl-6-(ethylamino)-2-propyl sulfanyl-7H-purin-8-one(compound 52d). 9-Benzyl-6-(propylamino)-2-propylsulfanyl-7H-purin-8-one(400 mg, compound 55b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 374.

Step 3: Preparation of9-benzyl-6-(propylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 9-benzyl-6-(propylamino)-2-propyl sulfinyl-7H-purin-8-one(compound 55b) instead of 6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one (compound 15f).9-Benzyl-6-(propylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one (113.5mg, Example 55) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm: 10.67 (s, 1H), 7.45-7.19 (m, 5H), 7.16-7.01 (m, 1H), 4.97 (s,2H), 4.17 (s, 1H), 3.52-3.40 (m, 2H), 3.36-3.28 (m, 2H), 1.81-1.44 (m,4H), 1.06-0.79 (m, 6H). MS obs. (ESI⁺) [(M+H)⁺]: 389.

Example 569-Benzyl-6-(isopropylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of9-benzyl-6-(isopropylamino)-2-propylsulfanyl-7H-purin-8-one

Compound 56a was prepared in analogy to Example 52, Step 4 by usingpropan-2-amine instead of EtNH₂.HCl.9-Benzyl-6-(isopropylamino)-2-propyl sulfanyl-7H-purin-8-one (1.5 g,compound 56a) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:358.

Step 2: Preparation of9-benzyl-6-(isopropylamino)-2-propylsulfinyl-7H-purin-8-one

Compound 56b was prepared in analogy to Example 52, Step 5 by using9-benzyl-6-(isopropyl amino)-2-propyl sulfanyl-7H-purin-8-one (compound56a) instead of 9-benzyl-6-(ethylamino)-2-propyl sulfanyl-7H-purin-8-one(compound 52d).9-Benzyl-6-(isopropylamino)-2-propylsulfinyl-7H-purin-8-one (1.35 g,compound 56b) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:373.

Step 3. Preparation of9-benzyl-6-(isopropylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 9-benzyl-6-(isopropyl amino)-2-propyl sulfinyl-7H-purin-8-one(compound 56b) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 15f).9-Benzyl-6-(isopropylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one (100mg, Example 56) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm: 10.45 (br. s., 1H), 7.47-7.21 (m, 5H), 6.93-6.80 (m, 1H), 4.95(s, 2H), 4.26-4.17 (m, 1H), 4.14 (s, 1H), 3.38-3.37 (m, 2H), 1.65-1.55(m, 2H), 1.23 (dd, J=6.4, 2.1 Hz, 6H), 0.92 (t, J=8.0 Hz, 3H). MS obsd.(ESI⁺) [(M+H)⁺]: 389.

Example 579-Benzyl-6-(cyclopropylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of9-benzyl-6-(cyclopropylamino)-2-propylsulfanyl-7H-purin-8-one

Compound 57a was prepared in analogy to Example 52, Step 4 by usingcyclopropanamine instead of EtNH₂.HCl.9-Benzyl-6-(cyclopropylamino)-2-propyl sulfanyl-7H-purin-8-one (1.35 g,compound 57a) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:356.

Step 2: Preparation of9-benzyl-6-(cyclopropylamino)-2-propylsulfinyl-7H-purin-8-one

Compound 57b was prepared in analogy to Example 52, Step 5 by using9-benzyl-6-(cyclopropylamino)-2-propyl sulfanyl-7H-purin-8-one insteadof 9-benzyl-6-(ethylamino)-2-propyl sulfanyl-7H-purin-8-one (52d).9-Benzyl-6-(cyclopropylamino)-2-propylsulfinyl-7H-purin-8-one (1.35 g,compound 57b) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:372

Step 3: Preparation of9-benzyl-6-(cyclopropylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 15, Step 7 byusing 9-benzyl-6-(cyclopropylamino)-2-propylsulfinyl-7H-purin-8-one(compound 57b) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 15f).9-Benzyl-6-(cyclopropylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one(30.5 mg, Example 57) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 7.40-7.57 (m, 1H), 7.28-7.34 (m, 5H), 4.97 (s, 2H), 4.12(s, 1H), 3.38-3.40 (m, 2H), 1.65-1.70 (m, 2H), 0.94 (t, J=8.0 Hz, 3H),0.80-0.81 (m, 2H), 0.52-0.59 (m, 2H). MS obsd. (ESI⁺) [(M+H)⁺]: 387.

Example 58N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-propyl-pentanamide

Step 1: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-propyl-pentanamide

To a 50 mL microwave vial was added6-amino-9-[(4-chlorophenyl)methyl]-2-propylsulfanyl-7H-8-one (2.2 g,6.29 mmol, compound 9c), 2-propylpentanoic anhydride (17 g, 62.9 mmol)and sulfuric acid (308 mg, 3.14 mmol). The vial was sealed and heated inthe microwave at 70° C. for 10 min. Then the reaction mixture wasdiluted with H₂O (50 mL) and neutralized with saturated sodiumbicarbonate solution. The mixture was extracted with DCM. The organiclayer was dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, 40 g, 100%DCM) to giveN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-propyl-pentanamide(2.9 g, compound 58a) as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 476.

Step 2: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-propyl-pentanamide

Compound 58b was prepared in analogy to Example 15, Step 6 by usingN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-propyl-pentanamide(2.9 g, compound 58a) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 15e).N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-propyl-pentanamide(2.8 g, compound 58b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 492.

Step 3: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-propyl-pentanamide

The title compound was prepared in analogy to Example 15, Step 7 byusingN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-propyl-pentanamide(compound 58b) instead of6-amino-9-[(2-chlorophenyl)methyl]-2-propylsulfinyl-7H-purin-8-one(compound 15f). N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-propyl-pentanamide (21 mg, Example 58)was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 11.15(s, 1H), 10.45 (br. s, 1H), 7.39 (s, 4H), 5.04 (s, 2H), 4.27 (s, 1H),3.37-3.44 (m, 2H), 2.68-2.73 (m, 1H), 1.56-1.65 (m, 4H), 1.24-1.42 (m,6H), 0.90 (t, J=8 Hz, 3H), 0.88 (t, J=8 Hz, 6H). MS obsd. (ESI⁺)[(M+H)⁺]: 507.

Example 59N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]acetamide

Step 1: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]acetamide

Compound 59a was prepared in analogy to Example 58, Step 1 by usingacetyl acetate instead of 2-propylpentanoic anhydride.N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]acetamide(300 mg, compound 59a) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 392.

Step 2: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]acetamide

Compound 59b was prepared in analogy to Example 58, Step 2 by usingN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]acetamide(300 mg, 0.76 mmol, compound 59a) instead ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-propyl-pentanamide(compound 58a).N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]acetamide(260 mg, compound 59b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 408.

Step 3: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]acetamide

Compound 59 was prepared in analogy to Example 50, Step 3 by usingN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]acetamide(250 mg, 0.61 mmol, compound 59b) instead ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-propyl-pentanamide(compound 58b).N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]acetamide(47 mg, Example 59) was obtained as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 11.04 (br. s, 1H), 10.34 (s, 1H), 7.40(s, 4H), 5.03 (s, 2H), 4.29 (s, 1H), 3.37-3.44 (m, 2H), 2.16 (s, 3H),1.60-1.66 (m, 2H), 0.91 (t, J=8 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 423.

Example 60N-[9-Benzyl-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]pentanamide

Step 1: Preparation ofN-(9-benzyl-8-oxo-2-propylsulfanyl-7H-purin-6-yl)pentanamide

Compound 60a was prepared in analogy to Example 58, Step 1 by usingpentanoyl pentanoate (TCI, Catalog number: V0006-25ML) and6-amino-9-benzyl-2-propylsulfanyl-7H-purin-8-one (Example 50) instead of2-propylpentanoic anhydride and6-amino-9-[(4-chlorophenyl)methyl]-2-propylsulfanyl-7H-purin-8-one(compound 9c).N-(9-benzyl-8-oxo-2-propylsulfanyl-7H-purin-6-yl)pentanamide (320 mg,compound 60a) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:400.

Step 2: Preparation ofN-(9-benzyl-8-oxo-2-propylsulfinyl-7H-purin-6-yl)pentanamide

Compound 60b was prepared in analogy to Example 58, Step 2 by usingN-(9-benzyl-8-oxo-2-propylsulfanyl-7H-purin-6-yl)pentanamide (310 mg,0.77 mmol, compound 60a) instead ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-propyl-pentanamide (compound 58a).N-(9-benzyl-8-oxo-2-propylsulfinyl-7H-purin-6-yl)pentanamide (276 mg,compound 60b) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:416.

Step 3: Preparation ofN-[9-benzyl-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]pentanamide

Compound 60 was prepared in analogy to Example 58, Step 3 by usingN-(9-benzyl-8-oxo-2-propylsulfinyl-7H-purin-6-yl)pentanamide (200 mg,0.48 mmol, compound 60b) instead ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-propyl-pentanamide (compound 58b).N-[9-benzyl-8-oxo-2-(propyl sulfonimidoyl)-7H-purin-6-yl]pentanamide (28mg, Example 60) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm: 10.98 (s, 1H), 7.27-7.39 (m, 5H), 5.04 (s, 2H), 4.27 (br. s.,1H), 3.24-3.44 (m, 2H), 2.46 (t, J=8.0 Hz, 2H), 1.58-1.71 (m, 4H),1.32-1.37 (m, 2H), 0.90-0.93 (m, 6H). MS obsd. (ESI⁺) [(M+H)⁺]: 431.

Example 61N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-ethyl-butanamide

Step 1: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-ethyl-butanamide

Compound 61a was prepared in analogy to Example 58, Step 1 by using2-ethylbutanoyl 2-ethylbutanoate instead of 2-propylpentanoic anhydride.N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-ethyl-butanamide(150 mg, compound 61a) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 448.

Step 2: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-ethyl-butanamide

Compound 61b was prepared in analogy to Example 58, Step 2 by usingN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-ethyl-butanamide(136 mg, 0.30 mmol, compound 61a) instead ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-propyl-pentanamide (compound 58a).N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-ethyl-butanamide(126 mg, compound 61b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 464.

Step 3: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-ethyl-butanamide

Compound 61 was prepared in analogy to Example 58, Step 3 by usingN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-ethyl-butanamide(200 mg, 0.43 mmol, compound 61b) instead ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-propyl-pentanamide(compound 58b).N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-ethyl-butanamide(39 mg, Example 61) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 11.15 (br. s., 1H), 10.50 (br. s., 1H), 7.36-7.41 (m,4H), 5.05 (s, 2H), 4.22-4.36 (m, 1H), 3.29-3.40 (m, 2H), 2.67 (d, J=1.8Hz, 1H), 1.43-1.69 (m, 4H), 1.15-1.38 (m, 2H), 0.86-0.94 (m, 9H). MSobsd. (ESI⁺) [(M+H)⁺]: 479.

Example 62N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-3-methyl-butanamide

Step 1: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-3-methyl-butanamide

Compound 62a was prepared in analogy to Example 58, Step 1 by using2-methylbutanoyl 2-methylbutanoate (J&K, Catalog number: j20-038361-25g) instead of 2-propylpentanoic anhydride.N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-methyl-butanamide(390 mg, compound 62a) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 434.

Step 2: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-3-methyl-butanamide

Compound 62b was prepared in analogy to Example 58, Step 2 by usingN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-methyl-butanamide(390 mg, 0.90 mmol, compound 62a) instead ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-propyl-pentanamide (compound 58a).N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-methyl-butanamide(390 mg, compound 62b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 450.

Step 3: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-3-methyl-butanamide

Example 62 was prepared in analogy to Example 58, Step 3 by usingN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-methyl-butanamide(390 mg, 0.87 mmol, compound 62b) instead ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-propyl-pentanamide(compound 58b).N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-methyl-butanamide(89 mg, Example 62) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ□ppm: 11.07 (br. s., 1H), 10.58 (br. s., 1H), 7.36-7.43 (m,4H), 5.05 (s, 2H), 4.29 (s, 1H), 3.30-3.37 (m, 2H), 2.36 (d, J=7.0 Hz,2H), 2.05-2.19 (m, 1H), 1.63 (sxt, J=7.6 Hz, 2H), 0.89-0.99 (m, 9H). MSobsd. (ESI⁺) [(M+H)⁺]: 465.

Example 63N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-methyl-pentanamide

Step 1: Preparation of 2-methylpentanoyl 2-methylpentanoate

In a 250 mL three-necked flask, 2-methylpentanoic acid (116 .g, 99.9mmol). Di-tert-butyl dicarbonate (10.9 g, 49.9 mmol) and magnesiumchloride (951 mg, 9.99 mmol) were dissolved in THF (100 mL) to give acolorless solution. The reaction mixture was stirred at 25° C. for 20hrs. The reaction mixture was poured into H₂O (100 mL) and extractedwith EtOAc (50 mL) three times. The organic layer was dried over MgSO₄and concentrated in vacuo to give 2-methylpentanoyl-2-methylpentanoate(19 g, compound 63a) as a light yellow oil which was used in the nextstep without further purification.

Step 2: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-methyl-pentanamide

Compound 63b was prepared in analogy to Example 58, Step 1 by using2-methylpentanoyl 2-methylpentanoate (compound 63b) instead of2-propylpentanoic anhydride.N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-methyl-pentanamide(330 mg, compound 63b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 448.

Step 3: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-methyl-pentanamide

Compound 63c was prepared in analogy to Example 58, Step 2 by usingN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-methyl-pentanamide(compound 63b) instead ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-propyl-pentanamide(compound 58a).N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-methyl-pentanamide(250 mg, compound 63c) as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]: 464.

Step 4: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-methyl-pentanamide

Example 63 was prepared in analogy to Example 58, Step 3 by usingN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-methyl-pentanamide(250 mg, 0.87 mmol, compound 63c) instead ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-propyl-pentanamide (compound 58b).N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-methyl-pentanamide(122 mg, Example 63) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm:11.1 (s, 1H), 10.6 (s, 1H), 7.40 (m, 4H), 5.05 (s, 2H), 4.30 (s, 1H),3.32-3.42 (m, 2H), 2.68-2.82 (m, 1H), 1.54-1.74 (m, 2H), 1.23-1.43 (m,4H), 1.13 (d, J=8.0 Hz, 3H), 0.91 (t, J=7.2 Hz, 6H). MS obsd. (ESI⁺)[(M+H)⁺]: 479.

Example 64N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2,2-dimethyl-propanamide

Step 1: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2,2-dimethyl-propanamide

Compound 64a was prepared in analogy to Example 58, Step 1 by using2,2-dimethylpropanoyl 2,2-dimethylpropanoate (TCI, Catalog number:P1414-25ML) instead of 2-propylpentanoic anhydride.N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2,2-dimethyl-propanamide(400 mg, compound 64a) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 434.

Step 2: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2,2-dimethyl-propanamide

Compound 64b was prepared in analogy to Example 58, Step 2 by usingN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2,2-dimethyl-propanamide(compound 64a) instead ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-propyl-pentanamide(compound 58a).N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2,2-dimethyl-propanamide(250 mg, compound 64b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 450.

Step 3: Preparation ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2,2-dimethyl-propanamide(64)

Example 64 was prepared in analogy to Example 58, Step 3 by usingN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2,2-dimethyl-propanamide(compound 64b) instead ofN-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-propyl-pentanamide(compound 58b).N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2,2-dimethyl-propanamide(33.5 mg, Example 64) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 10.96 (s, 1H), 10.60 (s, 1H), 7.41 (m, 4H), 5.06 (s,2H), 4.31 (s, 1H), 3.35-3.47 (m, 2H), 1.57-1.65 (m, 2H), 1.26 (m, 9H,0.91 (t, J=8.0 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 465.

Example 65N-[9-Benzyl-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-propyl-pentanamide

Step 1: Preparation ofN-(9-benzyl-8-oxo-2-propylsulfanyl-7H-purin-6-yl)-2-propyl-pentanamide(65a)

Compound 65a was prepared in analogy to Example 58, Step 1 by using6-amino-9-benzyl-2-propylsulfanyl-7H-purin-8-one (compound 4a) insteadof 6-amino-9-benzyl-2-propylsulfanyl-7H-purin-8-one (compound 9c).N-(9-Benzyl-8-oxo-2-propylsulfanyl-7H-purin-6-yl)-2-propyl-pentanamide(500 mg, compound 65a) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 442.

Step 2: Preparation ofN-(9-benzyl-8-oxo-2-propylsulfinyl-7H-purin-6-yl)-2-propyl-pentanamide

Compound 65b was prepared in analogy to Example 58, Step 2 by usingN-(9-benzyl-8-oxo-2-propylsulfanyl-7H-purin-6-yl)-2-propyl-pentanamide(compound 65a) instead of N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfanyl-7H-purin-6-yl]-2-propyl-pentanamide (compound 50a).N-(9-benzyl-8-oxo-2-propylsulfinyl-7H-purin-6-yl)-2-propyl-pentanamide(400 mg, compound 65b) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 458.

Step 3: Preparation ofN-[9-Benzyl-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-propyl-pentanamide

Example 65 was prepared in analogy to Example 58, Step 3 by usingN-(9-benzyl-8-oxo-2-propyl sulfinyl-7H-purin-6-yl)-2-propyl-pentanamide(compound 65b) instead of N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-propylsulfinyl-7H-purin-6-yl]-2-propyl-pentanamide (compound 58b).N-[9-Benzyl-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-propyl-pentanamide (25 mg, Example 65)was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 11.15(br. s., 1H), 10.45 (br. s., 1H), 7.27-7.39 (m, 5H), 5.06 (s, 2H), 4.29(s, 1H), 3.31-3.37 (m, 2H), 2.61-2.87 (m, 1H), 1.50-1.75 (m, 4H),1.23-1.43 (m, 6H), 0.81-0.97 (m, 9H). MS obsd. (ESI⁺) [(M+H)⁺]: 473.

Example 66[6-Amino-9-benzyl-2-(methylsulfonimidoyl)-8-oxo-purin-7-yl]methylacetate

To a solution of 6-amino-9-benzyl-2-(methylsulfonimidoyl)-7H-purin-8-one(300 mg, 0.94 mmol, Example 1) in DMF (5 mL) was added NaH (45 mg, 1.13mmol). The reaction was stirred for 10 min, then chloromethyl acetate(123 mg, 1.13 mmol) was added. The reaction mixture was stirred at RTfor 0.5 hr, then quenched with sat. NH₄Cl and concentrated in vacuo. Theresidue was purified by prep-HPLC to give[6-amino-9-benzyl-2-(methylsulfonimidoyl)-8-oxo-purin-7-yl]methylacetate (8.3 mg, Example 66) as a white solid. ¹H NMR (400 MHz, CD₃OD) δppm: 7.48-7.35 (m, 2H), 7.33-7.26 (m, 3H), 6.01 (s, 2H), 5.12 (s, 2H),3.35-3.33 (m, 3H), 2.11 (s, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 391.

Example 67[6-Amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purin-7-yl]methyl acetate

The title compound was prepared in analogy to Example 66 by using6-amino-9-benzyl-2-(propyl sulfonimidoyl)-7H-purin-8-one (Example 4)instead of 6-amino-9-benzyl-2-(methyl sulfonimidoyl)-7H-purin-8-one(Example 1). [6-Amino-9-benzyl-2-(propylsulfonimidoyl)purin-8-yl]N-ethyl-N-methyl-carbamate (15 mg, Example 67) was obtained as a whitesolid. ¹H NMR (400 MHz, CD₃OD) δ ppm: 7.45-7.43 (m, 2H), 7.35-7.28 (m,3H), 6.01 (s, 2H), 5.12 (s, 2H), 3.55-3.44 (m, 2H), 2.12 (s, 3H),1.81-1.74 (m, 2H), 1.02 (t, J=7.2 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]:419.

Example 68[6-Amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purin-7-yl]methyl2,2-dimethylpropanoate

The title compound was prepared in analogy to Example 66 by using6-amino-9-benzyl-2-(propylsulfonimidoyl)-7H-purin-8-one (Example 4) andchloromethyl 2,2-dimethylpropanoate instead of6-amino-9-benzyl-2-(methyl sulfonimidoyl)-7H-purin-8-one (Example 1) andchloromethyl acetate.[6-Amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purin-7-yl]methyl2,2-dimethylpropanoate (15.8 mg, Example 68) was obtained as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.48-7.50 (m, 2H), 7.31-7.36 (m,3H), 6.01 (s, 2H), 5.95 (s, 2H), 5.12 (s, 2H), 3.58-3.44 (m, 2H),1.85-1.94 (m, 2H), 1.24 (s, 9H), 1.07 (t, J=7.12 Hz, 3H). MS obsd.(ESI⁺) [(M+H)⁺]: 461.

Example 691-[6-Amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purin-7-yl]ethylacetate

Step 1: Preparation of 1-Chloroethyl Acetate

To a flask containing freshly dried catalytic amount of ZnCl₂ (680 mg, 5mmol) under nitrogen was added acetyl chloride (3.9 g, 50 mmol) and themixture was cooled to −5° C. to −10° C. Acetaldehyde (2.4 g, 55 mmol)was added dropwise and the resulting reaction mixture stirred at 22-33°C. for 1 hr. The mixture was concentrated in vacuo to afford1-chloroethyl acetate which was used in the next step without furtherpurification.

Step 2: Preparation of1-[6-amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purin-7-yl]ethylacetate

The title compound was prepared in analogy to Example 66 by using6-amino-9-benzyl-2-(propyl sulfonimidoyl)-7H-purin-8-one (Example 4) and1-chloroethyl acetate instead of 6-amino-9-benzyl-2-(methylsulfonimidoyl)-7H-purin-8-one (Example 1) and chloromethyl acetate.1-[6-Amino-9-benzyl-8-oxo-2-(propyl sulfonimidoyl)purin-7-yl]ethylacetate (9.3 mg, Example 69) was obtained as a white solid. ¹H NMR (400MHz, CD₃OD) δ ppm: 7.44-7.30 (m, 5H), 7.05-7.03 (m, 1H), 5.12 (s, 2H),3.33 (br. s., 2H), 2.14 (s, 3H), 1.74 (m, 2H), 1.72 (d, J=6.8 Hz, 3H),1.04-1.00 (m, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 433.

Example 706-Amino-9-[(4-chlorophenyl)methyl]-2-(ethylsulfonimidoyl)-7H-purin-8-one

Step 1: Preparation of6-amino-9-[(4-chlorophenyl)methyl]-2-ethylsulfanyl-7H-purin-8-one

Compound 70a was prepared in analogy to Example 1, Step 3 by usingiodoethane and6-amino-9-[(4-chlorophenyl)methyl]-2-sulfanyl-7H-purin-8-one (compound9b) instead of methyl iodide and6-amino-9-phenylmethyl-2-sulfanyl-7H-purin-8-one (compound 1b).6-Amino-9-[(4-chlorophenyl)methyl]-2-ethylsulfanyl-7H-purin-8-one (2.5g, compound 70a) was obtained as a white solid. MS obsd. (ESI⁺)[(M+H)⁺]: 336.

Step 2: Preparation of6-amino-9-(4-chlorobenzyl)-2-ethylsulfinyl-7H-purin-8-one

Compound 70b was prepared in analogy to Example 1, Step 4 by using6-amino-9-[(4-chlorophenyl)methyl]-2-ethyl sulfanyl-7H-purin-8-one(compound 70a) instead of 6-amino-9-benzyl-2-methylsulfanyl-7H-purin-8-one (compound 1c).6-Amino-9-(4-chlorobenzyl)-2-ethylsulfinyl-7H-purin-8-one (1.94 g,compound 70b) was obtained as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]:352.

Step 3: Preparation of6-amino-9-[(4-chlorophenyl)methyl]-2-(ethylsulfonimidoyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 1, Step 5 by using6-amino-9-(4-chlorobenzyl)-2-ethyl sulfinyl-7H-purin-8-one (compound70b) instead of 6-amino-9-benzyl-2-(2-methyl sulfinyl)-7H-purin-8-one(compound 1d).6-Amino-9-[(4-chlorophenyl)methyl]-2-(ethylsulfonimidoyl)-7H-purin-8-one(217 mg, Example 70) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 10.61 (s, 1H), 7.42-7.35 (m, 4H), 6.98 (s, 2H), 4.96 (s,2H), 4.05 (s, 1H), 3.42-3.37 (m, 2H), 1.16 (t, J=7.4 Hz, 3H). MS obsd.(ESI⁺) [(M+H)⁺]: 367.

Separation of compound of Example 70 by chiral HPLC afforded Example70-A (faster eluting, 31.8 mg) and Example 70-B (slower eluting, 10 mg)as white solid. (Separation condition: methanol 5%-40% (0.05% DEA)/CO₂on ChiralPak IC-3 column.)

Example 70-A

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.76 (s, 1H), 7.45-7.33 (m, 4H), 7.01(s, 2H), 4.96 (s, 2H), 4.03 (s, 1H), 3.40-3.34 (m, 2H), 1.17 (t, J=7.4Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 367.

Example 70-B

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.70 (s, 1H), 7.46-7.28 (m, 4H), 7.01(s, 2H), 4.96 (s, 2H), 4.03 (s, 1H), 3.44-3.36 (m, 2H), 1.17 (t, J=7.4Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]: 367.

Example 716-Amino-2-(ethylsulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one

Step 1: Preparation of4-amino-2-oxo-3-(p-tolylmethyl)-1H-imidazole-5-carbonitrile

Compound 71a was prepared in analogy to Example 9, Step 1 by usingp-tolylmethanamine instead of 4-chloropenylmethylamine.4-Amino-2-oxo-3-(p-tolylmethyl)-1H-imidazole-5-carbonitrile (26.6 g,compound 71a) was obtained as a grey solid and used directly in nextstep without further purification. MS obsd. (ESI⁺) [(M+H)⁺]: 229.

Step 2: Preparation of6-amino-9-(p-tolylmethyl)-2-sulfanyl-7H-purin-8-one

Compound 71b was prepared in analogy to Example 9, Step 2 by using of4-amino-2-oxo-3-(p-tolylmethyl)-1H-imidazole-5-carbonitrile (compound71a) instead of4-amino-3-[(4-chlorophenyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile(compound 9a). 6-Amino-9-(p-tolylmethyl)-2-sulfanyl-7H-purin-8-one (20.0g, compound 71b) was obtained as a yellow solid. MS obsd. (ESI⁺)[(M+H)⁺]: 288.

Step 3: Preparation of6-amino-2-ethylsulfanyl-9-(p-tolylmethyl)-7H-purin-8-one

Compound 71c was prepared in analogy to Example 1, Step 3 by using6-amino-9-(p-tolylmethyl)-2-sulfanyl-7H-purin-8-one (compound 71b) andiodoethane instead of 6-amino-9-benzyl-2-ethylsulfanyl-7H-purin-8-one(compound 2a) and methyl iodide.6-Amino-2-ethylsulfanyl-9-(p-tolylmethyl)-7H-purin-8-one (13 g, compound71c) was obtained as a yellow solid. MS obsd. (ESI⁺) [(M+H)⁺]: 316.

Step 4: Preparation of6-amino-2-ethylsulfinyl-9-(p-tolylmethyl)-7H-purin-8-one

Compound 71d was prepared in analogy to Example 1, Step 4 by using6-amino-2-ethyl sulfanyl-9-(p-tolylmethyl)-7H-purin-8-one (compound 71c)instead of 6-amino-9-benzyl-2-methyl sulfanyl-7H-purin-8-one (compound1c). 6-Amino-2-ethylsulfinyl-9-(p-tolylmethyl)-7H-purin-8-one6 (3.5 g,compound 71d) was obtained as a yellow solid. MS obsd. (ESI⁺) [(M+H)⁺]:332.

Step 5: Preparation of6-amino-2-(ethylsulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one

The title compound was prepared in analogy to Example 1, Step 5 by using6-amino-2-ethylsulfinyl-9-(p-tolylmethyl)-7H-purin-8-one (compound 71d)instead of 6-amino-9-benzyl-2-methyl sulfinyl-7H-purin-8-one (compound1d). 6-Amino-2-(ethylsulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one(530 mg, Example 71) was obtained as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 10.53 (s, 1H), 7.24 (d, J=8.03 Hz, 2H), 7.13 (d, J=8.03Hz, 2H), 6.94 (br. s., 2H), 4.91 (s, 2H), 4.03 (s, 1H), 3.36-3.41 (m,2H), 2.26 (s, 3H), 1.18 (t, J=7.28 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]:347.

Separation of compound of Example 71 by chiral HPLC afforded Example71-A (faster eluting, 56.8 mg) and Example 71-B (slower eluting, 56.7mg) as white solid. (Separation condition: methanol 5%-40% (0.05%DEA)/CO₂ on ChiralPak AD-3 column.)

Example 71-A

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.52 (br. s., 1H), 7.24 (d, J=8.0 Hz,2H), 7.13 (d, J=7.9 Hz, 2H), 6.94 (br. s., 2H), 4.91 (s, 2H), 4.02 (s,1H), 3.43-3.33 (m, 2H), 2.26 (s, 3H), 1.18 (t, J=7.3 Hz, 3H). MS obsd.(ESI⁺) [(M+H)⁺]: 347.

Example 71-B

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.52 (br. s., 1H), 7.24 (d, J=8.0 Hz,2H), 7.13 (d, J=8.0 Hz, 2H), 6.94 (br. s., 2H), 4.91 (s, 2H) 4.02 (s,1H), 3.42-3.33 (m, 2H), 2.26 (s, 3H), 1.18 (t, J=7.3 Hz, 3H). MS obsd.(ESI⁺) [(M+H)⁺]: 347.

Example 726-Amino-2-(ethylsulfonimidoyl)-9-[(4-fluorophenyl)methyl]-7H-purin-8-one

Step 1: Preparation of4-amino-3-[(4-fluorophenyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile

Compound 72a was prepared in analogy to Example 9, Step 1 by using(4-fluorophenyl)methylamine instead of 4-chloropenylmethylamine.4-Amino-3-[(4-fluorophenyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile (48g, compound 72a) was obtained as a light yellow solid and used directlyin next step without further purification. MS obsd. (ESI⁺) [(M+H)⁺]:233.

Step 2: Preparation of6-amino-9-[(4-fluorophenyl)methyl]-2-sulfanyl-7H-purin-8-one

Compound 72b was prepared in analogy to Example 9, Step 2 by using of4-amino-3-[(4-fluorophenyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile(compound 72a) instead of4-amino-3-[(4-chlorophenyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile(compound 9a).6-Amino-9-[(4-fluorophenyl)methyl]-2-sulfanyl-7H-purin-8-one (32.0 g,compound 72b) was obtained as a yellow solid. MS obsd. (ESI⁺) [(M+H)⁺]:292.

Step 3: Preparation of6-amino-2-ethylsulfanyl-9-[(4-fluorophenyl)methyl]-7H-purin-8-one

Compound 72c was prepared in analogy to Example 1, Step 3 by using6-amino-9-[(4-fluorophenyl)methyl]-2-sulfanyl-7H-purin-8-one (compound72b) and iodoethane instead of6-amino-9-benzyl-2-sulfanyl-7H-purin-8-one (compound 1b) and methyliodide.6-Amino-2-ethylsulfanyl-9-[(4-fluorophenyl)methyl]-7H-purin-8-one (5.6g, compound 72c) was obtained as a yellow solid. MS obsd. (ESI⁺)[(M+H)⁺]: 320.

Step 4: Preparation of6-amino-2-ethylsulfinyl-9-[(4-fluorophenyl)methyl]-7H-purin-8-one

Compound 72d was prepared in analogy to Example 1, Step 4 by using6-amino-2-ethylsulfanyl-9-[(4-fluorophenyl)methyl]-7H-purin-8-one(compound 72c) instead of 6-amino-9-benzyl-2-methylsulfanyl-7H-purin-8-one (compound 1c).6-Amino-2-ethylsulfinyl-9-[(4-fluorophenyl)methyl]-7H-purin-8-one (4.8g, compound 72d) was obtained as a yellow solid. MS obsd. (ESI⁺)[(M+H)⁺]: 332.

Step 5: Preparation of6-amino-2-(ethylsulfonimidoyl)-9-[(4-fluorophenyl)methyl]-7H-purin-8-one

The title compound was prepared in analogy to Example 1, Step 5 by using6-amino-2-ethyl sulfinyl-9-[(4-fluorophenyl)methyl]-7H-purin-8-one(compound 72d) instead of6-amino-9-benzyl-2-methylsulfinyl-7H-purin-8-one (compound 1d).6-Amino-2-(ethylsulfonimidoyl)-9-[(4-fluorophenyl)methyl]-7H-purin-8-one(2.9 g, Example 72) was obtained as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 10.57 (br. s., 1H), 7.40 (dd, J=8.5, 5.5 Hz, 2H), 7.16(t, J=8.9 Hz, 2H), 6.97 (br. s., 2H), 4.94 (s, 2H), 4.07 (s, 1H),3.43-3.36 (m, 2H), 1.17 (t, J=7.4 Hz, 3H). MS obsd. (ESI⁺) [(M+H)⁺]:351.

Separation of compound of Example 72 by chiral HPLC afforded Example72-A (faster eluting, 85.4 mg) and Example 72-B (slower eluting, 36.4mg) as white solid. (Separation condition: methanol 5%-40% (0.05%DEA)/CO₂ on ChiralPak AD-3 column.)

Example 72-A

¹H NMR (400 MHz, DMSO-d₆) ppm: 10.53 (br. s., 1H), 7.41 (dd, J=8.5, 5.5Hz, 2H), 7.17 (t, J=8.9 Hz, 2H), 6.98 (br. s., 2H), 4.95 (s, 2H), 4.07(s, 1H), 3.45-3.36 (m, 2H), 1.17 (t, J=7.3 Hz, 3H). MS obsd. (ESI⁺)[(M+H)⁺]: 351.

Example 72-B

¹H NMR (400 MHz, DMSO-d₆) ppm: 10.53 (br. s., 1H), 7.41 (dd, J=8.5, 5.5Hz, 2H), 7.17 (t, J=8.9 Hz, 2H), 6.98 (br. s., 2H), 4.95 (s, 2H), 4.07(s, 1H), 3.44-3.37 (m, 2H) 1.17 (t, J=7.3 Hz, 3H). MS obsd. (ESI⁺)[(M+H)⁺]: 351.

Example 73: HEK-Blue-hTLR 7 Cells Assay

A stable HEK-Blue-hTLR7 cell line was purchased from InvivoGen (Cat. #:hkb-htlr7, San Diego, Calif., USA). These cells were designed forstudying the stimulation of human TLR7 by monitoring the activation ofNF-κB. A SEAP (secreted embryonic alkaline phosphatase) reporter genewas placed under the control of the IFN-3 minimal promoter fused to fiveNF-κB and AP-1-binding sites. The SEAP was induced by activating NF-κBand AP-1 via stimulating HEK-Blue-hTLR7 cells with TLR7 ligands.Therefore the reporter expression was regulated by the NF-κB promoterupon stimulation of human TLR7 for 20 hrs. The cell culture supernatantSEAP reporter activity was determined using QUANTI-Blue™ kit (Cat. #:rep-qbl, Invivogen, San Diego, Ca, USA) at a wavelength of 640 nm, adetection medium that turns purple or blue in the presence of alkalinephosphatase.

HEK-Blue-hTLR7 cells were incubated at a density of 250,000-450,000cells/mL in a volume of 180 μL in a 96-well plate in Dulbecco's ModifiedEagle's medium (DMEM) containing 4.5 g/L glucose, 50 U/mL penicillin, 50mg/mL streptomycin, 100 mg/mL Normocin, 2 mM L-glutamine, 10% (V/V)heat-inactivated fetal bovine serum for 24 hrs. Then the HEK-Blue-hTLR-7cells were incubated with addition of 20 μL test compound in a serialdilution in the presence of final DMSO at 1% and perform incubationunder 37° C. in a CO₂ incubator for 20 hrs. Then 20 μL of thesupernatant from each well was incubated with 180 L Quanti-bluesubstrate solution at 37° C. for 2 hrs and the absorbance was read at620-655 nm using a spectrophotometer. The signalling pathway that TLR7activation leads to downstream NF-κB activation has been widelyaccepted, and therefore similar reporter assay was also widely used forevaluating TLR7 agonist (Tsuneyasu Kaisho and Takashi Tanaka, Trends inImmunology, Volume 29, Issue 7, July 2008, Pages 329.sci; Hiroaki Hemmiet al, Nature Immunology 3, 196-200 (2002)).

The compounds of the present invention were tested in HEK-Blue-hTLR7assay for their TLR7 agonism activity as described herein and resultsare listed in Table 1. The Examples were found to have EC₅₀ of about0.01 μM to about 0.7 μM. Particular compounds of the present inventionwere found to have EC₅₀ of about 0.01 μM to about 0.1 μM.

TABLE 1 Activity of Compounds in HEK-Blue-hTLR7 assay in vitro HEK-Blue-hTLR7 (EC₅₀ Example No. (μM)) GS-9620 0.80 S-1 0.37 P-2 0.27 P-5 3.14  10.30  1-B 0.18  2 0.20  3 0.33  3-A 0.27  3-B 0.55  4 0.065  4-A 0.067 4-B 0.086  5 0.32  6 0.43  7 0.18  9 0.012  9-A 0.014  9-B 0.011 100.074 11 0.066 13 0.043 14 0.017 15 0.19 16 0.22 16-A 0.76 16-B 0.15 170.068 18 0.047 19 0.67 20 0.26 22 0.042 23 0.016 24 0.037 25 0.0096 260.021 27 0.036 28 0.021 29 0.027 29-A 0.019 29-B 0.022 30 0.018 31 0.04032 0.054 33 0.066 34 0.030 35 0.12 36 0.022 37 0.023 38 0.075 39 0.17 400.15 41 0.084 42 0.09 43 0.24 44 0.136 70 0.057 70-A 0.054 70-B 0.077 710.098 71-A 0.134 71-B 0.087

Example 74: HEK-Blue-hTLR8 Cells Assay and Selectivity Index(EC_(50(TLR8))/EC_(50(TLR7)))

A stable HEK-Blue-hTLR8 cell line was purchased from InvivoGen (Cat. #:HEK-Blue-htlr8, San Diego, Calif., USA). These cells were designed forstudying the stimulation of human TLR8 by monitoring the activation ofNF-κB. A SEAP (secreted embryonic alkaline phosphatase) reporter genewas placed under the control of the IFN-3 minimal promoter fused to fiveNF-κB and AP-1-binding sites. The SEAP was induced by activating NF-κBand AP-1 via stimulating HEK-Blue-hTLR8 cells with TLR8 ligands.Therefore the reporter expression was regulated by the NF-κB promoterupon stimulation of human TLR8 for 20 hrs. The cell culture supernatantSEAP reporter activity was determined using QUANTI-Blue™ kit (Cat. #:rep-qb 1, Invivogen, San Diego, Ca, USA) at a wavelength of 640 nm, adetection medium that turns purple or blue in the presence of alkalinephosphatase.

HEK-Blue-hTLR8 cells were incubated at a density of 250,000-450,000cells/mL in a volume of 180 μL in a 96-well plate in Dulbecco's ModifiedEagle's medium (DMEM) containing 4.5 g/L glucose, 50 U/mL penicillin, 50mg/mL streptomycin, 100 mg/mL Normocin, 2 mM L-glutamine, 10% (V/V)heat-inactivated fetal bovine serum for 24 hrs. Then the HEK-Blue-hTLR8cells were incubated with addition of 20 μL test compound in a serialdilution in the presence of final DMSO at 1% and perform incubationunder 37° C. in a CO₂ incubator for 20 hrs. Then 20 μL of thesupernatant from each well was incubated with 180 μL Quanti-bluesubstrate solution at 37° C. for 2 hours and the absorbance was read at620-655 nm using a spectrophotometer. The signalling pathway that TLR8activation leads to downstream NF-κB activation has been widelyaccepted, and therefore similar reporter assay was also widely used forevaluating TLR8 agonist (Tsuneyasu Kaisho and Takashi Tanaka, Trends inImmunology, Volume 29, Issue 7, July 2008, Pages 329.sci; Hiroaki Hemmiet al, Nature Immunology 3, 196-200 (2002)).

The compounds of the present invention were tested in HEK-Blue-hTLR8assay for their TLR8 agonism activity as described herein and resultsare listed in Table 2. The ratio of TLR8 agonism activity compared toTLR7 agonism activity was defined as the selectivity index (EC₅₀ (TLR8)value/EC50 (TLR7) value) and calculated accordingly. Since TLR7 and TLR8agonists differ in their target cell selectivity and cytokine inductionprofile, and TLR7-specific agonists activate plasmacytoid DCs (pDCs) andB cells and induce mainly IFN-α and IFN-regulated cytokines, which maybe potentially beneficial as the HBV therapy. The higher selectivityindex the compound shows, the more TLR7 specific the compound is. Thecompounds of present invention showed comparable or better selectivityindex over reference compounds.

TABLE 2 Activity of Compounds in HEK Blue-hTLR-8 assay in vitro andselective index HEK Blue hTLR-8 Example No. EC50 (μM) Selective indexGS-9620 11.6 14 S-1 >1000 >2703 P-2 >1000 >3707 P-5 >1000 >318  1 652.42175  1-B 535.7 2976 13 300 6977 16 >1000 >4546 20 >1000 >3846 70 90.01579 70-A >1000 >18518

Example 75: Lysa Solubility

LYSA solubility assay is used to determine the aqueous solubility of acompound.

Samples were prepared in duplicate from 10 mM DMSO stock solution. Afterevaporation of DMSO with a centrifugal vacuum evaporator, the compoundswere dissolved in 0.05 M phosphate buffer (pH 6.5), stirred for one hourand shaken for two hours. After one night, the solutions were filteredusing a microtiter filter plate. Then the filtrate and its 1/10 dilutionwere analyzed by HPLC-UV. In addition a four-point calibration curve wasprepared from the 10 mM stock solutions and used for the solubilitydetermination of the compounds. The results are in μg/mL and summarizedin Table 3. Compounds with higher solubility could broaden itssuitability for different dosage forms and increase the chance toachieve desired concentration in systemic circulation, which in turn canpotentially lower the required dose. The exemplified compounds ofpresent invention showed much improved solubility compared to S-1, P-2and P-5.

TABLE 3 Solubility data of compounds of present invention LYSA ExampleNo. (μg/mL) S-1 0.5 P-2 1 P-5 1  1-A 85  1-B 98  2 29  3 300  4 21  4-A56  4-B 50  5 40  6 89  7 18 11 18 13 10 18 166 19 >428 21 121 24 12 277 29-A 6 29-B 11 32 18 33 79 39 >520 40 168 43 >465 44 357 70 7 70-B 571 12 71-A 13 71-B 13 72 152 72-A 90 72-B 115

Example 76: Metabolic Stability in Human Liver Microsomes

The human microsomal stability assay is used for early assessment ofmetabolic stability of a test compound in human liver microsomes.

Human liver microsomes (Cat. NO.: 452117, Corning, USA; Cat. NO.: H2610,Xenotech, USA) were preincubated with test compound for 10 minutes at37° C. in 100 mM potassium phosphate buffer, pH 7.4. The reactions wereinitiated by adding NADPH regenerating system. The final incubationmixtures contained 1 μM test compound, 0.5 mg/mL liver microsomalprotein, 1 mM MgCL₂, 1 mM NADP, 1 unit/mL isocitric dehydrogenase and 6mM isocitric acid in 100 mM potassium phosphate buffer, pH 7.4. Afterincubation times of 0, 3, 6, 9, 15 and 30 minutes at 37° C., 300 μL ofcold ACN (including internal standard) was added to 100 μL incubationmixture to terminate the reaction. Following precipitation andcentrifugation, the amount of compound remaining in the samples weredetermined by LC-MS/MS. Controls of no NADPH regenerating system at zeroand 30 minutes were also prepared and analyzed. The results werecategorized as: low (<7.0 mL/min/kg), medium (7.0-16.2 mL/min/kg) andhigh (16.2-23.2 mL/min/kg). Results of metabolic stability study inhuman liver microsomes are given in Table 4. Exemplified compounds ofthis invention showed low clearance in human liver microsomes, whilereference compounds GS-9620 and P-2 were categorized as high and mediumrespectively.

TABLE 4 Metabolic stability in human liver microsomes of compounds ofthis invention. Human Liver Microsome Example No. Clearance (mL/min/kg)GS-9620 17.8 P-2 7.3  1 <6.15*  1-A <6.15  1-B <6.15  2 <6.15  3 <6.15 3-A <6.15  4 <6.15  5 <6.15 29-A <6.15 31 <6.15 32 <6.15 33 <6.15 34<6.15 35 <6.15 37 <6.15 39 <6.15 40 <6.15 43 <6.15 44 <6.15 70-A <6.1570-B <6.15 71-A <6.15 71-B <6.15 72 <6.15 72-A <6.15 72-B <6.15 *6.15mL/min/kg is the limitation of assay sensitivity.

Example 77: Cytochrome P450 (Cyp450) Induction Screening Assay mRNAInduction

Induction of cytochrome P450 enzymes is associated with an increasedprevalence of clinical drug-drug interactions. The clinical consequencesof induction may be therapeutic failure caused by a decreased systemicexposure of the drug itself or a co-administered therapy, or toxicity asa result of increased bioactivation. Cytochrome P450 (CYP450) inductionassay has been used to understand the potential drug-drug interactionliabilities in drug discovery stage.

Cell Culture

Human cryopreserved hepatocytes (Life Technologies, Carlsbad, USA) werethawed and cultured in collagen I coated 96-well plates with a densityof 52,000 cells/well. After attachment, hepatocyte maintenance medium(HMM; Lonza, Switzerland) was changed after cells were pre-culturedovernight.

Test compounds were dosed to the cells next morning at an indicatedconcentration (up to 10 μM) in HMM culture medium containing gentamycinand a constant 0.1% DMSO. Similarly, dilutions of the positive inducercompounds omeprazole (prototypical inducer of human CYP1A2; finalconcentrations: 1 and 10 μM), phenobarbital (prototypical inducer ofhuman CYP2B6; final concentrations: 100 and 1000 μM) and rifampicin(prototypical inducer of human CYP3A4; final concentrations: 1 and 10μM) were prepared from 1000 fold DMSO stock solutions in HMM containinggentamycin. Medium change was then performed and cells were exposed for24 hours to test compounds, positive inducer compounds, or vehicle (0.1%DMSO), respectively.

At the end of the compound exposure period, medium was removed and cellslysed using 100 μL/well MagNA Pure LC RNA isolation tissue lysis buffer(Roche Diagnostics AG, Rotkreuz, Switzerland). Plates were then sealedand frozen at −80° C. until further workup.

mRNA Isolation, Processing and qRT-PCR

mRNA isolation was performed using the MagNA Pure 96 system (RocheDiagnostics AG, Rotkreuz, Switzerland) and the respective cellular RNAlarge volume kit (Roche Diagnostics AG, Rotkreuz, Switzerland) fromthawed samples diluted 1:1 with PBS. The volume of the cell lysis and anelution volume of 100 μL were used. 20 μL of the resulting mRNAsuspension was then used for reverse transcription using 20 μL of thetranscript or first stand cDNA synthesis kit (Roche prime Supply,Mannheim, Germany). The resulting cDNA was diluted with 40 μL of H₂Obefore using for qRT-PCR. qRT-PCR was performed by using the forward andthe reverse primer, the corresponding Universal Probe Library (all fromMicrosynth, Balgach, Switzerland) and the Taqman Fast advanced mastermix (Applied Biosystems), on an ABI 7900 machine (Applied Biosystems).

Calculations

qRT-PCR Ct-values for the respective P450s were put into relation to theCt-value of RN18S1 (microsynth, Balgach, Switzerland) of the samesample. Doing so, a respective Δct-value was calculated. Using theaverage of all Δct-values for the vehicle control samples, a ΔΔct-valuewas calculated for each sample(ΔΔct-value(sample)=Δct-value(sample)−average of Δct-value of allvehicle controls). The fold induction of the respective sample wascalculated as 2{circumflex over ( )}(−ΔΔct). The individual foldinduction values were then averaged per treatment condition (usually n=3biological replicates).

Relative induction values to the respective positive inducer compoundcondition (10 μM omeprazole for CYP1A2; 1000 μM Phenobarbital forCYP2B6; 10 μM Rifampicin for CYP3A4) were then calculated from the foldinduction values as follows:

Relative induction (%)=100×(T−V)/(P−V)

-   -   T: fold induction of test compound condition    -   P: fold induction of positive inducer compound    -   V: fold induction of vehicle controls

Results of CYP3A4 induction are given in Table 5. Exemplified compoundsof present invention did not cause a significant change in CYP 3A4 mRNAat any concentration. The results indicated that exemplified compoundshad no CYP induction liability, which can avoid potential druginteraction in clinical application.

TABLE 5 Relative induction values of compounds of present invention to10 μM Rifampicin Relative induction of Positive control Example No. (10μM Rifampicin) (%)  4-A −0.63  4-B −0.90 24 −0.72 70-A 0.42 70-B −0.4271-A −0.10

Example 78: Ames Microsuspension Assay

The Ames microsuspension assay examines if a compound causes DNAmutations. The method was based on a modified pre-incubation versiondescribed by Kado et al (see references: B. N. Ames, J. McCann, E.Yamasaki, Mutation Res. 1975, 31, 347-364 N.Y. Kado, D. Langley, and E.Eisenstadt, Mutation Res. 1983, 121, 25-32). Five Salmonella typhimuriumtester strains (TA1535, TA97, TA98, TA100, and TA102) were treated withthe test compound in absence and in presence of an exogenous metabolicactivation system (S9). The bacteria were pre-incubated for 1 h, thepre-incubation volume is 210 μL (100 μL of overnight culture, 100 μL ofS9 mix (10% S9) or 100 μL phosphate buffer, and 10 μL test compoundsolution). The overnight cultures were resuspended for the test in coldphosphate buffer. The S9 mix contains potassium chloride, magnesiumchloride, sodium phosphate buffered saline, NADP⁺ andglucose-6-phosphate. The test tubes are incubated and shaken for 60minutes at 37° C. 2.2 mL soft agar supplemented with L-histidine andbiotin was added afterwards and the content of the tubes were mixed andpoured on Vogel-Bonner minimal agar plates.

Three replicate plates for the test compound and negative control or tworeplicate plates for the positive controls were incubated at 37° C.,upside down, for 2 days. Colonies were counted electronically using anautomatic image analysis system after having inspected the backgroundlawn for signs of toxicity. Plates exhibiting precipitate orcontamination were counted manually.

S9 is an in vitro metabolic system which is obtained from liverhomogenates by centrifuging them at 9000 g for 20 minutes. It containsCYP450 isoforms, phase-II metabolic enzymes, etc. In the Amesmicrosuspension assay test, S9 is used to assess mutagenicity ofcompounds, some of which require metabolic activation to becomemutagenic.

Criteria of the Ames microsuspension assay: a positive result is definedas a reproducible, dose-related increase in the number of revertantcolonies in at least one of the strains. For TA1535 and TA98, thepositive threshold is a 2-fold increase over control. For TA97, TA100and TA102, the threshold is a 1.5-fold increase.

Results of Ames microsuspension assay are given in Table 6. Exemplifiedcompounds of present invention showed negative results suggesting thatthere was no indication of mutagenicity of the compounds tested in theAmes microsuspension assay.

TABLE 6 Ames microsuspension assay results Compound NO. Ames result  1-Bnegative  4 negative  4-A negative  4-B negative  9 negative 27 negative29-A negative 29-B negative 34 negative 39 negative 70-A negative 70-Bnegative 71-A negative

Example 79: hERG Channel Inhibition Assay

The hERG channel inhibition assay is a highly sensitive measurement thatidentifies compounds exhibiting hERG inhibition related tocardiotoxicity in vivo. The hERG K⁺ channels were cloned in humans andstably expressed in a CHO (Chinese hamster ovary) cell line. CHO_(hERG)cells were used for patch-clamp (voltage-clamp, whole-cell) experiments.Cells were stimulated by a voltage pattern to activate hERG channels andconduct IKh_(ERG) currents (rapid delayed outward rectifier potassiumcurrent of the hERG channel). After the cells were stabilized for a fewminutes, the amplitude and kinetics of IK_(ERG) were recorded at astimulation frequency of 0.1 Hz (6 bpm). Thereafter, the test compoundwas added to the preparation at increasing concentrations. For eachconcentration, an attempt was made to reach a steady-state effect,usually, this was achieved within 3-10 min at which time the nexthighest concentration was applied. The amplitude and kinetics ofI_(KhERG) are recorded in each concentration of the drug which werecompared to the control values (taken as 100%). (references: Redfern WS, Carlsson L, Davis A S, Lynch W G, MacKenzie I, Palethorpe S, Siegl PK, Strang I, Sullivan A T, Wallis R, Camm A J, Hammond T G. 2003;Relationships between preclinical cardiac electrophysiology, clinical QTinterval prolongation and torsade de pointes for a broad range of drugs:evidence for a provisional safety margin in drug development.Cardiovasc. Res. 58:32-45, Sanguinetti M C, Tristani-Firouzi M. 2006;hERG potassium channels and cardiac arrhythmia. Nature 440:463-469,Webster R, Leishman D, Walker D. 2002; Towards a drug concentrationeffect relationship for QT prolongation and torsades de pointes. Curr.Opin. Drug Discov. Devel. 5:116-26).

Results of hERG are given in Table 7. A safety ratio (hERG IC₂₀/EC₅₀)>30suggests a low potential of bERG related cardiotoxicity.

TABLE 7 hERG results and safety ratio. Compound hERG hERG Safety ratioNO. IC₂₀ (μM) IC₅₀ (μM) (hERG IC₂₀/EC₅₀)  1-B >10 >20 >56 4 >10 >20 >154  4-A >10 >20 >149  4-B >10 >20 >116  9 >10 >20 >83327 >10 >20 >278 29-A >10 >20 >526 29-B >10 >20 >546 34 >10 >20 >33339 >10 >20 >59 71-A >10 >20 >75

Example 80: GSH Adduct Screening Assay

The formation of reactive metabolites is an unwanted drug propertybecause of the idiosyncratic clinical adverse effect. GSH adductformation is used to evaluate the formation of reactive metabolites invitro. Positive controls were Diclofenac, Troglitazone, Nefazodone andmGluR5. Solvent control was DMSO.

Incubation

All compounds including positive and solvent control were incubatedusing a 96-deep-well plate (Eppendorf) at 20 μM (addition of 1 μL of 10mM DMSO stock solution) in 450 μL of 0.1 M sodium phosphate buffer at pH7.4 containing rat liver microsomes (RLM) and human liver microsomes(HLM). Microsomal protein concentration is 1 mg/mL. Pipetting wasperformed using a TECAN pipetting robot. The buffer was prepared at roomtemperature by combining 2.62 g NaH₂PO₄.1H₂O and 14.43 g Na₂HPO₄.2H₂Odissolved in H₂O (Millipore, >18 MΩ) to a weight of 1000 g (pH 7.4).After 5 minutes of pre-incubation at 37° C. the reaction was started byadding 50 μL of buffer containing GSH (100 mM) and NADPH (20 mM). Freshstock solutions of GSH and NADPH were prepared straight before eachexperiment. The final concentrations were 5 mM for GSH and 1 mM forNADPH. After 60 minutes of incubation at 37° C. (shaking at 800 rpm) thereaction is quenched with 500 μL of cold acetonitrile and centrifuged at5000×g at 25° C. for 11 minutes. Before LC-MS/MS analysis thesupernatant was split to two fractions, 450 μL and 400 μL each followedby evaporation using a N₂ stream at 35° C. to a volume of approximately150 μL.

Liquid Chromatography

Sample clean-up and chromatography of analytes were performed on-line bya column-switching set-up of two HPLC columns. From each sample 50 μLwere injected (Shimadzu SilHTC) and loaded with water containing 0.1%formic acid onto a trapping column (Waters Oasis HLB 2.1×10 mm, 25 μm)with a flow rate of 0.3 mL/min. After 1.5 min the trapped analytes werethen flushed (included a change in flow direction on the trappingcolumn) onto an analytical column (Waters Atlantis T3 2.1×100 mm, 3 μm)with a total flow of 0.2 mL/min starting with 95/5% water containing0.1% formic acid/acetonitrile. The fraction of acetonitrile wasincreased to 20% acetonitrile between 2 and 2.5 minutes, to 70% at 10minutes and to 98% at 11 minutes. After 12 minutes the analytical columnwas equilibrated to start conditions (5% acetonitrile). The trappingcolumn was washed with acetonitrile for 1 minute at a flow rate of 1.5mL/min and equilibrated for 1.25 minutes with water containing 0.1%formic acid at a flow rate of 1.5 mL/min. The total running time was 14min per sample.

Mass Spectrometry

A triple quadrupole-linear ion trap mass spectrometer 4000 Qtrapequipped with an electrospray ionization source (Turbo V) was used, bothfrom Applied Biosystems/MDS Sciex. Based on a published method ofDieckhaus et al. (2005) a precursor ion survey scan (PreIS) method wasused to detect GSH-conjugates in negative ion mode. Briefly, as surveyscan ions (400 to 900 amu within 2 seconds) are scanned for precursorsof m/z 272 amu, the ion spray voltage was −4200 V, the sourcetemperature 500° C., nitrogen was used as curtain and collision gas. Ifthe parent molecule exceeds a molecular mass of 500 the scan range waschanged to 500 amu to 1000 amu within 2 seconds. For signals in thesurvey scan exceeding 7500 cts (that was approximately 5 times of thebackground signal), enhanced resolution scan and enhanced product ionscan were triggered which allowed isotope determination and confirmationof a positive GSH adduct by the presence of diagnostic fragment ions.Further instrument settings were as following: Curtain gas: 30 psi, CADgas: 10 psi Gas 1: 30 psi, Gas 2: 50 psi, declustering potential: −70 V,entrance potential: −10 V, collision energy: −24 V, and cell exitpotential −15 V. Data acquisition was performed using Analyst 1.4.2,data analysis, i.e. sample control (solvent) comparisons were performedwith Metabolite ID 1.3 (Applied Biosystems/MDS Sciex). (reference:Dieckhaus, C. M., Fernandez-Metzler, C. L., King, R., Krolikowski, P.H., and Baillie, T. A. (2005). Negative ion tandem mass spectrometry forthe detection of glutathione conjugates. Chem Res Toxicol 18, 630-638).

Results of GSH are given in Table 8. Exemplified compounds of presentinvention showed no flag in GSH assay indicating that no potentialreactive metabolite formation which might lead to idiosyncratichepatotoxicity.

TABLE 8 GSH results Compound NO. GSH results*  4 No flag  4-A No flag 4-B No flag  9 No flag 27 No flag 29-A No flag 34 No flag 39 No flag70-A No flag 70-B No flag 71-A No flag *No Flag: no GSH adduct formationobserved when compared to control (DMSO).

Example 81: Comparison of the Mean Plasma Concentration and PKParameters after 1 mg/kg Intravenous Dosing to Rat

The single dose PK in Male Wister-Han Rats was performed to assesspharmacokinetic properties of tested compounds. Two groups of animalswere dosed via bolus intravenous (IV) of the respective compound. Bloodsamples (approximately 20 μL) were collected via Jugular vein or analternate site at 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 7 hr and 24hr post-dose for IV group. Blood samples were placed into tubescontaining EDTA-K2 anticoagulant and centrifuged at 5000 rpm for 6 minat 4° C. to separate plasma from the samples. Following centrifugation,the resulting plasma was transferred to clean tubes for bioanalysis onLC/MS/MS. The pharmacokinetic parameters were calculated usingnon-compartmental module of WinNonlin® Professional 6.2.

Results of PK parameters are given in Table 9. Exemplified compounds ofpresent invention clearly showed unexpected superior PK profile on C0,CL and AUC compared to GS-9620 and S-1 in rat PK study with 5-10 foldshigher C0, 3-5 folds lower systemic clearance (CL) and 5-10 folds higherexposure (AUC). Therefore, compounds of present invention potentiallycould lead to less dose frequency and lower dose in clinicalapplication.

TABLE 9 the mean plasma concentration and PK parameters Mean plasmaconcentration (nM) Dose compound Example Example Example GS-9620* S-170-A 70-B 71-A Test Compound Example Example Example GS-9620 S-1 70-A70-B 71-A Time (h) IV (1mpk) IV (1mpk) IV (1mpk) IV (1mpk) IV (1mpk)   0.083 170 534 3052 2782 1848   0.25 102 236 1342 1434 1003   0.5 65.4125 718 862 537 1 48.1 38 354 461 292 2 21.6 9 110 173 115 4 13 ND 20.529.1 18.2  8** 4.17 ND 6.28 16.7 ND 24  ND ND ND ND ND C0 (nM) 220 5343052 2782 1848 CL 205 261 56 48.7 84.6 (mL/min/kg) AUC0-inf 201 201 16271894 1182 (nM · hr) *GS-9620 data were available from WO2016023511. **7hrs for Example 70-A, Example 70-B and Example 71-A.

1. A compound of formula (I),

wherein: R¹ is C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₇cylcoalkylC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl or pyrrolidinylC₁₋₆alkyl; R² is C₁₋₆alkyl,phenylC₁₋₆alkyl, pyridinylC₁₋₆alkyl or pyrimidinylC₁₋₆alkyl, saidphenylC₁₋₆alkyl, pyridinylC₁₋₆alkyl and pyrimidinylC₁₋₆alkyl areunsubstituted or substituted by one, two or three substituentsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆alkoxy, cyano,carboxy, carbamoyl, haloC₁₋₆alkyl, C₁₋₆alkylsulfonyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkoxyC₁₋₆alkylaminocarbonyl,pyrrolidinylcarbonyl and piperidinylcarbonyl; and R³ is H; orpharmaceutically acceptable salt, enantiomer or diastereomer thereof. 2.A compound according to claim 1, wherein: R¹ is methyl, ethyl, propyl,butyl, chloropropyl, cyclohexylmethyl, methoxyethyl, methoxypropyl,pyrrolidinylpropyl or trifluoroethyl; R² is isobutyl, benzyl,chlorobenzyl, fluorobenzyl, bromobenzyl, chlorofluorobenzyl,chloromethylbenzyl, dichlorobenzyl, difluorobenzyl, methylbenzyl,methoxybenzyl, cyanobenzyl, carbamoylbenzyl, trifluoromethylbenzyl,methylsulfonylbenzyl, methoxycarbonylbenzyl, carboxybenzyl,methoxyethylaminocarbonylbenzyl, piperidinylcarbonylbenzyl,pyrrolidinylcarbonylbenzyl, pyridinylmethyl, chloropyridinylmethyl,methylpyridinylmethyl, pyrimidinylmethyl or methylpyrimidinylmethyl; andR³ is H; or a pharmaceutically acceptable salt, enantiomer ordiastereomer thereof.
 3. A compound according to claim 1, wherein R¹ isC₁₋₆alkyl, haloC₁₋₆alkyl or C₁₋₆alkoxyC₁₋₆alkyl.
 4. A compound accordingto claim 3, wherein R¹ is methyl, ethyl, propyl, butyl, chloropropyl,trifluoroethyl, methoxyethyl or methoxypropyl.
 5. A compound accordingto claim 3, wherein R¹ is C₁₋₆alkyl.
 6. A compound according to claim 2,wherein R¹ is methyl, ethyl or propyl.
 7. A compound according to claim6, wherein R¹ is ethyl.
 8. A compound according to claim 1, wherein R²is: phenylC₁₋₆alkyl, said phenylC₁₋₆alkyl is unsubstituted orsubstituted by halogen, carbamoyl, C₁₋₆alkyl, carboxy, cyano,C₁₋₆alkoxy, C₁₋₆alkylsulfonyl and C₁₋₆alkoxyC₁₋₆alkylaminocarbonyl;pyridinylC₁₋₆alkyl, said pyridinylC₁₋₆alkyl is unsubstituted orsubstituted by C₁₋₆alkyl; or pyrimidinylC₁₋₆alkyl, saidpyrimidinylC₁₋₆alkyl is unsubstituted or substituted by C₁₋₆alkyl.
 9. Acompound according to claim 8, wherein R² is benzyl, methylbenzyl,chlorobenzyl, fluorobenzyl, difluorobenzyl, cyanobenzyl, carboxybenzyl,methoxybenzyl, methylsulfonylbenzyl, methoxyethylaminocarbonylbenzyl,pyridinylmethyl, methylpyridinylmethyl, pyrimidinylmethyl ormethylpyrimidinylmethyl.
 10. A compound according to claim 9, wherein R²is benzyl, methylbenzyl, chlorobenzyl, fluorobenzyl, difluorobenzyl,carboxybenzyl or methylpyridinylmethyl.
 11. A compound according toclaim 10, wherein R² is methylbenzyl or chlorobenzyl.
 12. A compoundaccording to claim 1, wherein: R¹ is C₁₋₆alkyl or C₁₋₆alkoxyC₁₋₆alkyl;R² is phenylC₁₋₆alkyl, said phenylC₁₋₆alkyl is unsubstituted orsubstituted by halogen, carbamoyl, C₁₋₆alkyl, carboxy, cyano andC₁₋₆alkoxyC₁-6alkylaminocarbonyl; or pyrimidinylC₁₋₆alkyl, saidpyrimidinylC₁₋₆alkyl is unsubstituted or substituted by C₁₋₆alkyl; R³ isH.
 13. A compound according to claim 12, wherein: R¹ is methyl, ethyl,propyl, butyl or methoxyethyl; R² is benzyl, methylbenzyl, chlorobenzyl,fluorobenzyl, cyanobenzyl, carboxybenzyl,methoxyethylaminocarbonylbenzyl, pyrimidinylmethyl ormethylpyrimidinylmethyl; R³ is H.
 14. A compound according to claim 1,wherein: R¹ is C₁₋₆alkyl; R² is phenylC₁₋₆alkyl, said phenylC₁₋₆alkyl isunsubstituted or substituted by halogen or C₁₋₆alkyl; R³ is H.
 15. Acompound according to claim 14, wherein: R¹ is ethyl or propyl; R² isbenzyl, chlorobenzyl or methylbenzyl; R³ is H.
 16. A compound accordingto claim 1 selected from:6-Amino-9-benzyl-2-(methylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-benzyl-2-(ethyl sulfonimidoyl)-7H-purin-8-one;6-Amino-9-benzyl-2-(2-methoxyethyl sulfonimidoyl)-7H-purin-8-one;6-Amino-9-benzyl-2-(propyl sulfonimidoyl)-7H-purin-8-one;6-Amino-9-benzyl-2-(butylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-benzyl-2-(3-methoxypropyl sulfonimidoyl)-7H-purin-8-one;6-Amino-9-benzyl-2-(2,2,2-trifluoroethyl sulfonimidoyl)-7H-purin-8-one;6-Amino-9-benzyl-2-(cyclohexylmethylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(4-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(4-methoxyphenyl)methyl]-2-(methylsulfonimidoyl)-7H-purin-8-one; 6-Amino-2-(3-chloropropylsulfonimidoyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one;6-Amino-9-[(4-methoxyphenyl)methyl]-2-(3-pyrrolidin-1-ylpropylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(4-chlorophenyl)methyl]-2-(methylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(6-chloro-3-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(2-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-2-(methyl sulfonimidoyl)-9-(3-pyridylmethyl)-7H-purin-8-one;3-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzonitrile;3-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzamide;6-Amino-2-(methyl sulfonimidoyl)-9-(2-pyridylmethyl)-7H-purin-8-one;6-Amino-2-(methyl sulfonimidoyl)-9-(4-pyridylmethyl)-7H-purin-8-one;6-Amino-9-isobutyl-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(3-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-2-(propylsulfonimidoyl)-9-[[4-(trifluoromethyl)phenylmethyl]methyl]-7H-purin-8-one;6-Amino-9-[(4-fluorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(4-bromophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(3,4-dichlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-(3,4-difluorophenylmethyl)-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(4-chloro-3-methyl-phenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-2-(propylsulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one;6-Amino-9-[(4-chloro-3-fluorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(2,4-difluorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;4-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzonitrile;4-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzamide;6-Amino-9-[(6-methyl-3-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(2-methyl-4-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(3-chloro-4-methyl-phenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(4-methylsulfonylphenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;Methyl4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzoate;4-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzoicacid;4-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]-N-(2-methoxyethyl)benzamide;6-Amino-9-[[4-(piperidine-1-carbonyl)phenyl]methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-2-(S-propylsulfonimidoyl)-9-[[4-(pyrrolidine-1-carbonyl)phenyl]methyl]-7H-purin-8-one;6-Methyl-2-(propylsulfonimidoyl)-9-(pyrimidin-5-ylmethyl)-7H-purin-8-one;6-Methyl-9-[(2-methylpyrimidin-5-yl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(4-chlorophenyl)methyl]-2-(ethylsulfonimidoyl)-7H-purin-8-one; 6-Amino-2-(ethylsulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one; and 6-Amino-2-(ethylsulfonimidoyl)-9-[(4-fluorophenyl)methyl]-7H-purin-8-one.
 17. A compoundaccording to claim 1 selected from: 6-Amino-9-benzyl-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(4-chlorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(6-chloro-3-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(4-fluorophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(4-bromophenyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-2-(propylsulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one;6-Amino-9-[(6-methyl-3-pyridyl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;Methyl4-[[6-amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzoate;4-[[6-Amino-8-oxo-2-(propylsulfonimidoyl)-7H-purin-9-yl]methyl]benzoicacid; 6-Methyl-9-[(2-methylpyrimidin-5-yl)methyl]-2-(propylsulfonimidoyl)-7H-purin-8-one;6-Amino-9-[(4-chlorophenyl)methyl]-2-(ethylsulfonimidoyl)-7H-purin-8-one; and6-Amino-2-(ethylsulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one, or apharmaceutically acceptable salt, enantiomer or diastereomer thereof.18. A compound according to claim 1 selected from:6-Amino-9-[(4-chlorophenyl)methyl]-2-(ethylsulfonimidoyl)-7H-purin-8-one; and 6-Amino-2-(ethylsulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one.
 19. A compound offormula (Ia),

wherein: R⁴ is C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₇cylcoalkylC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl or pyrrolidinylC₁₋₆alkyl; R⁵ is C₁₋₆alkyl,phenylC₁₋₆alkyl, pyridinylC₁₋₆alkyl or pyrimidinylC₁₋₆alkyl, saidphenylC₁₋₆alkyl, pyridinylC₁₋₆alkyl and pyrimidinylC₁₋₆alkyl areunsubstituted or substituted by one, two or three substituentsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆alkoxy, cyano,carboxy, carbamoyl, haloC₁₋₆alkyl, C₁₋₆alkylsulfonyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkoxyC₁₋₆alkylaminocarbonyl,pyrrolidinylcarbonyl and piperidinylcarbonyl; R⁶ is H orC₁₋₆alkyl-C(O)O—C₁₋₆alkyl-; R⁷ is H, C₁₋₆alkyl, C₃₋₇cycloalkyl orC₁₋₁₀alkylcarbonyl; R⁸ is H, C₁₋₆alkylcarbonyl,carboxyC₁-6alkylcarbonyl, C₁₋₆alkyoxycarbonylC₁₋₆alkylcarbonyl orbenzoyl; provided that R⁶, R⁷ and R⁸ are not H simultaneously; or apharmaceutically acceptable salt, enantiomer or diastereomer thereof.20. A compound according to claim 19, wherein: R⁴ is methyl, ethyl,propyl, butyl, chloropropyl, cyclohexylmethyl, methoxyethyl,methoxypropyl, pyrrolidinylpropyl or trifluoroethyl; R⁵ is isobutyl,benzyl, chlorobenzyl, fluorobenzyl, bromobenzyl, chlorofluorobenzyl,chloromethylbenzyl, dichlorobenzyl, difluorobenzyl, methylbenzyl,methoxybenzyl, cyanobenzyl, carbamoylbenzyl, trifluoromethylbenzyl,methyl sulfonylbenzyl, methoxycarbonylbenzyl, carboxybenzyl,methoxyethylaminocarbonylbenzyl, piperidinylcarbonylbenzyl,pyrrolidinylcarbonylbenzyl, pyridinylmethyl, chloropyridinylmethyl,methylpyridinylmethyl, pyrimidinylmethyl or methylpyrimidinylmethyl; R⁶is H, acetoxymethyl, acetoxyethyl or dimethylpropanoyloxymethyl; R⁷ isH, ethyl, propyl, isopropyl, cyclopropyl, acetyl, pentanoyl,methylpentanoyl, propylpentanoyl, ethylbutanoyl, methylbutanoyl ordimethylpropanoyl; and R⁸ is H, acetyl, pentanoyl, carboxypropanoyl,ethoxycarbonylpropanoyl or benzoyl; provided that R⁶, R⁷ and R⁸ are notH simultaneously; or pharmaceutically acceptable salt, enantiomer ordiastereomer thereof.
 21. A compound according to claim 19, wherein R⁴is C₁₋₆alkyl.
 22. A compound according to claim 19, wherein R⁴ is methylor propyl.
 23. A compound according to claim 19, wherein R⁵ isphenylC₁₋₆alkyl or pyridinylC₁₋₆alkyl, said phenylC₁₋₆alkyl andpyridinylC₁₋₆alkyl are unsubstituted or substituted by one to threesubstituents independently selected from halogen or C₁₋₆alkyl.
 24. Acompound according to claim 23, wherein R⁵ is benzyl, chlorobenzyl ormethylpyridinylmethyl.
 25. A compound according to claim 19, wherein R⁷is H, C₁₋₆alkyl or C₁₋₁₀alkylcarbonyl.
 26. A compound according to claim25, wherein R⁷ is H, ethyl, propyl, methylpentanoyl or propylpentanoyl.27. A compound according to claim 19, wherein R⁸ is H, C₁₋₆alkylcarbonylor carboxyC₁₋₆alkylcarbonyl.
 28. A compound according to claim 27,wherein R⁸ is H, pentanoyl or carboxypropanoyl.
 29. A compound accordingto claim 19 selected from:N-[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]pentanamide;N-[[6-Amino-9-[(4-chlorophenyl)methyl]-8-oxo-7H-purin-2-yl]-oxo-propyl-λ⁴-sulfanylidene]acetamide;N-[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-methyl-oxo-λ⁴-sulfanylidene]acetamide;4-[[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]amino]-4-oxo-butanoicacid;4-[[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]amino]-4-oxo-butanoicacid;4-[[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]amino]-4-oxo-butanoicacid; Ethyl4-[[(6-amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]amino]-3-oxo-butanoate;Ethyl4-[[(6-amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]amino]-4-oxo-butanoate;Ethyl4-[[(6-amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]amino]-4-oxo-butanoate;N-[(6-amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]benzamide;N-[(6-Amino-9-benzyl-8-oxo-7H-purin-2-yl)-oxo-propyl-λ⁴-sulfanylidene]benzamide;9-Benzyl-6-(ethylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one; 6-(Ethylamino)-9-[(6-methyl-3-pyridyl)methyl]-2-(S-propylsulfonimidoyl)-7H-purin-8-one; 9-[(4-Chlorophenyl)methyl]-6-(ethylamino)-2-(propyl sulfonimidoyl)-7H-purin-8-one;9-Benzyl-6-(propylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one;9-Benzyl-6-(isopropylamino)-2-(propylsulfonimidoyl)-7H-purin-8-one;9-Benzyl-6-(cyclopropylamino)-2-(propyl sulfonimidoyl)-7H-purin-8-one;N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-propyl-pentanamide;N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]acetamide;N-[9-Benzyl-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]pentanamide;N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-ethyl-butanamide;N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-3-methyl-butanamide;N-[9-[(4-Chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-methyl-pentanamide;N-[9-[(4-chlorophenyl)methyl]-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2,2-dimethyl-propanamide;N-[9-Benzyl-8-oxo-2-(propylsulfonimidoyl)-7H-purin-6-yl]-2-propyl-pentanamide;[6-Amino-9-benzyl-2-(methyl sulfonimidoyl)-8-oxo-purin-7-yl]methylacetate;[6-Amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purin-7-yl]methylacetate;[6-Amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purin-7-yl]methyl2,2-dimethylpropanoate; and 1-[6-Amino-9-benzyl-8-oxo-2-(propylsulfonimidoyl)purin-7-yl]ethyl acetate.
 30. A process for thepreparation of a compound according to claim 1 comprising the followingsteps: (a) reacting a compound of formula (IIa),

with an imination reagent; (b) reacting a compound of formula (IIb),

with an imination reagent; wherein R^(a) is R¹ or R⁴, R^(b) is R² or R⁵,R⁷ is C₁₋₆alkyl or C₃₋₇cycloalkyl; (c) reacting a compound of formula(IIIc),

with an oxidant followed by an imination reagent, wherein R^(a) is R¹ orR⁴, R^(b) is R² or R⁵, R¹² is C₁₋₁₀alkyl; (d) reacting a compound offormula (IIIa),

with an oxidant followed by an imination reagent, wherein R^(a) is R¹ orR⁴, R^(b) is R² or R⁵; (e) reacting a compound of formula (Ie),

with haloester; and (f) reacting a compound of formula (Ie),

with carboxylic anhydride or acylchloride; wherein R¹, R², R⁴ and R⁵ aredefined as in
 1. 31. A compound or pharmaceutically acceptable salt,enantiomer or diastereomer according to any one of claims 1 to 29 foruse as therapeutically active substance.
 32. A pharmaceuticalcomposition comprising a compound in accordance with claim 1 and atherapeutically inert carrier.
 33. (canceled)
 34. (canceled)
 35. Amethod of agonising the TLR7 receptor, the method comprisingadministering a compound according to claim
 1. 36. A method of inducingproduction of interferon-α, which method comprises administering atherapeutically effective amount of a compound according to claim
 1. 37.(canceled)
 38. (canceled)
 39. A method for the treatment or prophylaxisof hepatitis B virus infection, which method comprises administering atherapeutically effective amount of a compound according to claim 1.